Reaction Discovery Using Neopentylene-Tethered Coupling Partners: Cycloisomerization/Oxidation of Electron-Deficient Dienynes

Article abstract of DOI:10.1021/acs.orglett.7b02261

A rhodium-catalyzed cycloisomerization and oxidation of tethered dienynes for the synthesis of indanes is described. An auxiliary fragmentation/olefination method (also described herein) provides novel access to tethered alkyne-dienoate substrates. The re

Full text of DOI:10.1021/acs.orglett.7b02261

Letter
pubs.acs.org/OrgLett
Reaction Discovery Using Neopentylene-Tethered Coupling Partners:
Cycloisomerization/Oxidation of Electron-Deficient Dienynes
Nicholas J. Kramer,† Tung T. Hoang,† and Gregory B. Dudley*,†,‡
†Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306, United States
‡C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, West Virginia 26505, United States
S
* Supporting Information
ABSTRACT: A rhodium-catalyzed cycloisomerization and oxidation
of tethered dienynes for the synthesis of indanes is described. An
auxiliary fragmentation/olefination method (also described herein)
provides novel access to tethered alkyne-dienoate substrates. The
reported method circumvents current limitations in and expands the
scope of inverse-demand Diels−Alder-type cycloadditions. Traditional
discovery substrates involving malonate-, ether-, and sulfonamide-
based tethers are problematic in the current methodology, under-
scoring the unique virtue of neopentylene-tethered substrates for
reaction discovery.
Scheme 1. Preliminary [4 + 2] Annulation of Neopentyl-
Tethered Dienyne 1
onsidering the rich history of the concerted Diels−Alder
1
Ccycloaddition, and modern advances in transition-metal
catalysis of alternative reaction pathways,2−7 strategic gaps in [4
+ 2] annulation technology can be viewed as fundamentally
problematic. Electron-deficient dienes, for example (unless
stabilized by aromaticity8), are limited by an underappreciated
tendency to react with electron-deficient dienophiles,9 which
often results in dimerization and/or oligomerization. Likewise,
alkyne dienophiles can be reticent cycloaddition partners,
perhaps because alkyne π-bonds are relatively shorter and
stronger than their alkene counterparts.10 Thus, “inverse-
demand”11 [4 + 2] cycloadditions of unactivated alkyne
dienophiles with electron-deficient dienoates present a
fundamental reactivity challenge,12−14 placing a strategic
limitation on [4 + 2] annulation technology. Here we report
a breakthrough methodology for intramolecular Diels−Alder
(IMDA)-type reactions of electron-deficient dienynes, using
neopentylene-tethered substrates and rhodium (Rh) catalysts.
We coupled Rh-catalyzed cycloisomerizations with in situ
oxidation to generate substituted indanes (Scheme 1). Notably,
traditional tethers featuring malonate, ether, and sulfonamide
functional groups compromise this process (vide infra).
Reaction discovery methodologies aimed at expanding the
scope and impact of [4 + 2] cycloadditions (Figure 1) often
begin with a focus on intramolecular processes of tethered
reaction partners, which provide favorable entropy as well as
synthetic utility for preparing polycyclic structures. Substrate
tethers are often chosen based on synthetic convenience. With
few exceptions,12 traditional tethers for intramolecular [4 + 2]
cycloaddition methodologies include malonate, ether, and
sulfonamide functional groups, which facilitate tethering via
SN2-type alkylation chemistry but compromise the ideal of
using a chemically inert tether.
We prepared neopentylene- and propylene-tethered dienoate
substrates (Scheme 2) by extension of our previously reported
tandem fragmentation/olefination methodology.15 Mixtures of
alcohols 4 and phosphonates 5 were treated with LDA at low
temperature. Lithiated 4 undergoes fragmentation upon
warming, and the resulting aldehyde reacts with the awaiting
lithio-phosphonate anion of 5. Our initial substrate scope
included variable methyl substitution on the alkyne, on the
tether, and/or on the dienoate to provide focused coverage of
representative dienoates. Other dienoates, including ones
bearing ether, malonate, and sulfonamide tethers,16 were
prepared by traditional methods.17
Our initial success with the oxidative cycloisomerization
came using Wilkinson’s catalyst (10 mol %) in toluene in a
sealed vial at 130 °C (cf. Scheme 1, above). These conditions
give rise to inseparable mixtures of (dihydro)indanes 2 and 3,
so air was bubbled through the reaction mixture after heating to
complete oxidation to 2. We later switched from air to DDQ
for more reliable oxidation. Preliminary screening of other
Received: July 24, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02261
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Rhodium-Catalyzed Cycloisomerization and
Oxidation of Tethered Alkyne Dienoates for the Synthesis of
a
Indanes
Figure 1. Variants of the Diels−Alder reaction, including inverse
electron demand (A) (IEDDA), (B) intramolecular (IMDA), (C)
metal-catalyzed formal (FDA), and (D) the dehydro Diels−Alder
reaction (DDA). (E) Cycloisomerization and oxidation reported in
this manuscript.
Scheme 2. Synthesis of Alkyl-Tethered Dienynes by Tandem
a
Fragmentation−Olefination
a
All yields are isolated yields from ∼0.4−0.5 mmol of starting material.
Higher catalyst loading: reactions performed using 10% [{RhCl-
b
(nbd)}2] and 20% AgSbF6 because little-to-no cyclization was
observed under the above conditions; see Table 1 for additional
c
discussion. Isolated product contains a trace impurity, observable in
1
the H and 13C NMR spectra.
and silyl-alkynes 1g and 1h (derived from dienyne 1a17) were
also good cyclization substrates, providing indanes 2g and 2h in
of 87% and 84% isolated yield, respectively. The highest yields
were obtained from the neopentylene-tethered substrates (cf.
2c vs 2e and 2d vs 2f), which we attribute to favorable
Thorpe−Ingold conformational biases18 imposed by the gem-
dimethyl substitutent pattern in the tether. In contrast,
substrates with traditional ether, malonate, and sulfonamide
tethers did not undergo cycloisomerization with similar
efficiency (without significantly increasing the amount of
catalyst; see Table 1, below).
a
All yield are isolated yields.
We next examined the disparity between neopentylene-
tethered systems and those bearing heteroatoms in the tether
metal (Au, Pd, Co, and Ni) catalysts failed to reveal a cheaper
and more efficient alternative to rhodium, and qualitative
screening of ligands helped us identify diene ligands,
particularly norbornadiene, as superior to the triphenylphos-
phine ligands of Wilkinson’s catalyst.
Table 1. Traditional Tether Cycloaddition Reaction
16
1
Progressions by H NMR
A cationic rhodium(I) norbornadiene catalystgenerated in
situ by combining [{RhCl(nbd)}2] with silver hexafluoroan-
timonate (AgSbF6) in dichloromethaneenabled us to lower
the temperature (from 130 °C to rt), time (from 3 h to 30
min), and catalyst loading (from 10% to 2% [Rh]) while
increasing the isolated yields of the desired indanes (cf. Scheme
3).
With the better optimized set of conditions, our next focus
was to elaborate on the scope of the cycloaddition and
oxidation sequence to access the Indane core (Scheme 3).
Oxidative cycloisomerization of the newly acquired hydro-
carbon-tethered alkyne dienoates (1a−f, cf. Scheme 2) provides
indanes 2a−f in good to excellent yields (Scheme 3). Bromo-
[{RhCl(nbd)}2] (mol %) % conversion, estimated
1
entry
X
:AgSbF6 (mol %)
by H NMR
1
2
3
4
5
6
N-Ts
1:2
13 (1k → 2k)
60 (1k → 2k)
28 (1j → 2j)
>95 (1j → 2j)
 (1i → 2i)
>95 (1i → 2i)
N-Ts
10:20
1:2
C(CO2Et)2
C(CO2Et)2
10:20
1:2
O
O
10:20
B
DOI: 10.1021/acs.orglett.7b02261
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(Table 1). Catalyst inhibition does not seem to be the problem;
addition of excess diethyl malonate to a representative reaction
mixture (1c → 2c, not shown) did not noticeably impact the
reaction process. Alternatively, heteroatoms in the tether may
deactivate the substrate through subtle inductive effects,19 while
also providing alternative substitution and/or elimination
pathways that may become competitive at higher temperatures.
We also consider the possibility of alternative binding motifs in
substrates bearing additional Lewis basic sites to be a potential
factor in the slower reaction rates. The relatively poor reactivity
of traditional substrates may be overcome at higher catalyst
concentration (Table 1). We examined reactions of substrates
bearing sulfonamide, malonate, and ether functional groups in
the tether at low and high catalyst loadings (2 mol % and 20
mol % [Rh], respectively). Little to no conversion was observed
with 2 mol % [Rh]conditions for which neopentylene-
tethered substrates underwent full conversion. Increasing the
catalyst loading to 20 mol % [Rh] led to 60% conversion for
the sulfonamide and full conversion for malonate and ether
substrates. Reactions listed in Table 1 are not optimized, and
focused optimization on substrates bearing traditional tethers
may lead to improved procedures for these particular classes of
substrates.20 These studies underscore the virtues of neo-
pentylene-tethered substrates for initial reaction discovery.
We envision a mechanism analogous to what has been
described previously for Rh-catalyzed cycloisomerization of
tethered dienynes (Figure 2).2a Initial coordination of Rh(I) to
Figure 3. Illudalane sesquiterpene natural products containing a core
gem-dimethylindane.
was previously prepared in 9 steps from isophorone as a key
intermediate in the first synthesis of alcyopterosin A.22
Tethered alkyne dienoates undergo cycloisomerization/
oxidation to substituted indanes in the presence of Rh(I)
catalysts. The present methodology reveals the unique virtues
of the neopentylene tether for reaction discovery, as it enabled
us to close a persistent and important gap in Diels−Alder-type
cycloaddition technology. Extension of previous tandem
fragmentation/olefination methodology provides access to
neopentylene-tethered dienyne substrates. This is the second
reaction process we have identified23 for which the neo-
pentylene tether was strategically important to reaction
discovery, and it is the first that involves transition metal
catalysis and mild reaction conditions. We expect neo-
pentylene-tethered substrates to enable a new wave of reaction
discovery and provide access to underexplored structure space.
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.7b02261.
Experimental procedures, spectroscopic characterization
1
data, copies of H and 13C NMR data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gregory.dudley@mail.wvu.edu.
ORCID
Gregory B. Dudley: 0000-0001-6133-3747
Notes
Figure 2. Postulated catalytic cycle. (A) Coordination of π-system
with cationic Rh(I), (B) oxidative addition to form 7-membered
Rh(III)-metallacycle, (C) reductive elimination.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation (CHE 1300722),
Florida State University, and West Virginia University for
support of this work. We thank Brooke Blair (FSU), Andrew
Huh (FSU), and Ron Ramsubhag (FSU) for general
contributions in the Dudley lab at FSU, including preparing
some starting materials.
the dieneyne system is followed by oxidative cyclization to a
vinyl(π-allyl)Rh(III) intermediate, which can undergo reductive
elimination to regenerate Rh(I) and release the dihydroindane
product, which is later oxidized. One can imagine that the initial
dienyne-[Rh] coordination is disfavored for electron-poor π-
systems, which can help explain why a cationic Rh(I) with
weakly bound ligands (e.g., [RhCl(nbd)]2/AgSbF6) is better
than Wilkinson’s catalyst [RhCl(Ph3P)3], the catalyst with
which we made the original discovery. Electronegative atoms
inductively decrease electron-density in the π-systemperhaps
more so than may be expected19consistent with the poor
reactivity of traditional dienyne substrates bearing electro-
negative atoms in the tether.
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D
DOI: 10.1021/acs.orglett.7b02261
Org. Lett. XXXX, XXX, XXX−XXX