A novel stereoselective [8+2] double cycloaddition route to hydronaphthalene ring systems

Article abstract of DOI:10.1016/j.tetlet.2016.05.059

Substituted hydronaphthalenes where each of the ten carbons of the two-ring system contains a functionality were obtained through a tandem [8+2] cycloaddition and base-catalyzed rearrangement process using dienylfurans and electron-deficient alkynes. If t

Full text of DOI:10.1016/j.tetlet.2016.05.059

Accepted Manuscript
A novel stereoselective [8+2] double cycloaddition route to hydronaphthalene
ring systems
Weijiang Ying, Lei Zhang, Paul A. Wiget, James W. Herndon
PII:
S0040-4039(16)30582-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.059
TETL 47678
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 April 2016
11 May 2016
16 May 2016
Please cite this article as: Ying, W., Zhang, L., Wiget, P.A., Herndon, J.W., A novel stereoselective [8+2] double
cycloaddition route to hydronaphthalene ring systems, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/
j.tetlet.2016.05.059
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A novel stereoselective [8+2] double cycloaddition route to hydronaphthalene ring systems
Weijiang Ying, Lei Zhang, Paul A. Wiget, and James W. Herndon*
Department of Chemistry and Biochemistry
New Mexico State University
Las Cruces, NM 88003 USA
jherndon@nmsu.edu
Abstract: Substituted hydronaphthalenes where each of the ten carbons of the two-ring system contains
functionality were obtained through a tandem [8+2] cycloaddition and base-catalyzed rearrangement process
using dienylfurans and electron-deficient alkynes. If the [8+2] process is conducted under solvent-free
conditions the process could be conducted in a single reaction flask without isolation of the
chromatographically sensitive [8+2] cycloadducts. A mechanism involving base catalysed alkene positional
isomerization followed by disrotatory electrocyclic ring closure was proposed for the key reaction step that
converts [8+2] cycloadducts to hydronaphthalenes. The products undergo selective ring opening-isomerization
processes upon treatment with Lewis acids.
Introduction
Furan-bridged ten-membered ring systems (e.g. 3a, Scheme 1) are readily accessed through [8+2]-cycloaddition
of electron-deficient alkynes [e.g. dimethylacetylene dicarboxylate (DMAD), 2] and dienylfurans1 (e.g. 1a) or
their isobenzofuran analogs.2 Although that process proceeds in relatively high yield, the products are
somewhat acid-sensitive and require tremendous care in their purification. The preferred purification method
was silica gel chromatography using triethylamine-treated silica gel. In some experimental runs, an
unanticipated minor compound, assigned as the fused oxanorbornene 4a, was obtained in addition to the [8+2]-
cycloadduct 3a. Compound 4a was never observed in the crude reaction mixture, thus suggesting that its
formation is an artifact of the chromatographic purification process. This product could be eliminated by
performing the chromatography purification quickly and avoiding excess triethylamine in the column
preparation. In this manuscript the scope, limit, and mechanism for the formation of compound 4a in a single
pot from the coupling of dienylfurans and electron-deficient alkynes is discussed. This process represents a
novel and unconventional stereoselective construction of densely functionalized hydronaphthalenes in a formal
[8+2]-double cycloaddition process. Densely functionalized cyclohexadiene and hydronaphthalene derivatives
are highly useful building blocks for preparation of medicinally-important derivatives featuring these ring
systems and their preparation has been the focus of numerous recent investigations.3 This ring system is most

unusual in that it contains a bicyclo[4.4.0]decatriene ring system where every carbon atom is functionalized yet
neither of the rings is aromatic.
Scheme 1
Results and Discussion
Initially the transformation of isolated [8+2]-cycloadduct 3a to compound 4a was investigated under the
assumption that triethylamine was causing the isomerization process. A reasonable mechanistic pathway is
base-catalyzed alkene isomerization to conjugated hexatriene derivative 5a followed by disrotatory 6
electrocyclic ring closure,4 which establishes the relative stereochemistry at the junction of the oxanorbornene
and cyclohexadiene rings. The stereochemistry of the other ester group was assigned based on the 4 Hz
coupling constant between the bridgehead H and the H alpha to the ester group, which is consistent with only
the indicated isomer. The alternative isomer is expected to exhibit nearly a 0 Hz coupling constant due to the
nearly 90o dihedral angle.5 This stereochemistry can result from protonation of the intermediate anion from the
less hindered side prior to rearrangement of the resulting hexatriene ring system.

Thorough examination of the conditions for the [8+2]-cycloaddition between dienylfuran 1a and DMAD
employing a variety of solvent systems, temperatures, and reactant ratios revealed that this process is most
efficient when performed as a neat process6 using a 2:1 molar ratio of DMAD and dienylfuran. If lesser
amounts of DMAD were employed, several unidentified byproducts were observed in the crude reaction
mixtures and substantially lower yields were observed. A convenient procedure was desired where the neat
reactants would be heated to the appropriate temperature for [8+2] cycloadduct formation and then a base
solution would be added to effect the rearrangement. Treatment of the crude [8+2] adduct/unreacted DMAD
mixture with triethylamine in dioxane at room temperature afforded mixtures of rearrangement products 4a and
double bond shift product 6a7 in moderate yield. None of the simple double bond shift isomer 5a was ever
observed in the reaction mixture. Vinylogous carbonate 6a is an alternative base-catalyzed alkene
isomerization product, which is more stable than the starting material due to the vinylogous carbonate linkage
and the furan resonance contribution. Next a determined effort to optimize the rearrangement process of 3a to
4a was attempted using variety of basic substances. Diisopropyl ethylamine and potassium t-butoxide were
ineffective at promoting the reaction. Use of DBU in THF or methanol afforded lower yields of rearrangement
products. The best yield of product was obtained using a dual base system of DBU and triethylamine in
dioxane at room temperature.
Scheme 2
The relative energetics of the observed isomerization products were examined computationally in the simplest
system 3-6h (Scheme 2). The vinylogous carbonate 6h is more stable than the alternative isomerization product

5h or the starting material 3h. Although alkene isomerization product 5h is higher in energy that [8+2]
cycloadduct 3h, its pericyclic rearrangement product 4h is the most stable of the products observed. Both of the
enolate precursors (8h and 9h) to 5h and 6h are equal in energy, which implies that the major reaction pathway
is the result of a kinetically controlled deprotonation followed by reprotonation and rapid electrocyclic ring
closure. The unobserved furan isomerization product 7h, the result of a formal 1,7 hydride shift, is the true
thermodynamic product however this compound was never observed.
Table 1. Scope and limit for tandem [8+2] cycloaddition and base catalyzed rearrangement leading to
hydronaphthalenes.
Entrya
R1
H
R2
R3
R4
H
H
H
H
H
R5
H
H
H
H
H
R6
H
H
H
H
H
H
H
H
H
H
H
Yield 4
62% 4a
Yield 3/6
11% 6a
1
R2,3 = -(CH2)4-
R2,3 = -(CH2)4-
R2,3 = -(CH2)4-
R2,3 = -(CH2)3-
R2,3 = -(CH2)6-
2
D
65% 4a-d1 Trace 6a
3
Me
H
66% 4b
6% 4c
N/A
0%
4
5
H
63% 4d
0% 4e
0%
6
H
H
CO2Et
R4,5 = -(CH2)4-
60% 3e
53% 3f
0%
7
H
H
CH2OH R4,5 = -(CH2)4-
0% 4f
8
H
H
CO2Et
H
H
H
H
H
H
H
H
71% 4g
62% 4h
67% 4i
0% 4j
9b,c
10
11
12c,d
H
H
H
H
H
0%
H
Ph
t-Bu
0%
H
65% 3j
0%
67% 4k
b
aUnless otherwise noted the [8+2]-segment of the reaction was conducted with no solvent. The [8+2]-segment
c
of the reaction was conducted in dioxane solvent at 0.5 M concentration of the dienylfuran. Yield is based on

isolated and previously prepared1 3 going to 4, the yield does not include the formation of 3. dethyl 4-oxopent-2-
ynoate used instead of DMAD.
Next the reaction was tested on a variety of dienylfuran substrates (see Table 1). The compound with deuterium
in place of hydrogen at C-2 of the dienylfuran (see entry 2) was far more selective for the formation of
rearrangement product 4a-d1 (65 % yield) with minimal formation of 6a, indicating a strong kinetic isotope
effect in the deprotonation event. As expected, the rearrangement product (4b, entry 3) using the methylfuran
substrate was the exclusive product since the competing pathway is blocked. Adduct 4b was a solid and after
growing suitable crystals, X-ray analysis confirmed the proposed structure. The reaction proceeded similarly
for the larger ring system (entry 5), however the smaller ring system (entry 4) was much less efficient. In this
case the crude [8+2]-product was especially prone to decomposition, which could account for the lowered yield.
In cases using substrates where the distal alkene group of the dienylfuran is within a ring system (entries 6-7)
the final product was the simple [8+2] cycloadducts (3e, 3f), indicating that the [8+2] cycloaddition process was
successful but the product does not undergo base-catalyzed rearrangement, and may reflect steric hindrance in
the deprotonation step or conformational changes in the orientation of C-H bonds forced by the ring system.
The highest yield for formation of 4 was observed with ester-substituted dienylfuran substrate in entry 8, which
directs the deprotonation process to the correct position and lacks the ring structure detrimental to the
isomerization as in entries 6-7. The minimally-substituted dienylfuran in entry 9 similarly afforded primarily
the rearranged compound 4h, however in this case the [8+2] event was not efficient using the neat solvent
conditions. The yield noted is only for the rearrangement step. The monosubstituted dienylfuran of entry 10
afforded only rearrangement product 4i however the analogous t-butyl substrate in entry 11 afforded only the
[8+2] cycloadducts 3j. This later case likely fails to rearrange due to severe eclipsing interactions between the
furan ring hydrogens and the t-butyl group, and the resulting conformation is unable to participate in the
rearrangement. The reaction using the unsymmetrical alkyne in entry 12 afforded the analogous rearrangement
product 4k. This latter reaction was performed on the isolated major isomer (depicted) from the [8+2]
cycloaddition.8
A brief survey of the reactivity of these intermediates was conducted. The reaction with Lewis acids led to the
ring opening product 10. Surprisingly, the exact same product was obtained from the attempted copper-
catalyzed nucleophilic addition to the oxanorbornene linkage.9 In this system the dominant pathway for the
intermediate allylic carbocation is the observed selective deprotonation product 10 and not the -deprotonation
product 11 typically observed in oxanorbornenes that can aromatize (after conversion to the phenol).10
A
conjugate deprotonation pathway was also observed in the copper-catalyzed nucleophilic addition process as
well.

Scheme 3
Summary and Conclusions
In summary, a novel single step synthesis of highly functionalized hydronaphthalene systems has been
presented employing readily available dienylfurans and electron-deficient acetylenes as starting materials. The
reaction proceeds through [8+2] cycloaddition followed by base catalyzed olefin isomerization followed by
transannular 1,3,5-hexatriene ring closure. The simple procedure requires heating the neat reacts followed by
addition of base and solvent to afford the final products without requirement to isolate the hydrolytically
sensitive [8+2] cycloadducts. The products undergo a selective ring opening deprotonation upon treatment with
various transition metal catalysts.
Acknowledgements
This work was supported by the National Institutes of Health (5SC1GM083693). The Bruker X8 X-ray
diffractometer was purchased via an NSF CRIF:MU award to The University of New Mexico, CHE-0443580.
We thank Dr. Diane Dickie for X-ray data collection.
Supplementary Material
Complete experimental procedures, spectral characterization, and X-ray crystallography data.
References
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Graphical Abstract

Highlights
One-step formation of densely functionalized naphthalenes in one reaction flask
Novel rearrangement of [8+2] cycloaddition products via transannular 1,3,5-hexatriene ring
closure
Selective isomerization to triene-alcohols upon treatment with Lewis acids