The chemistry of thiophene-based bis-(p-quinodimethanes): An approach to macrocycles

Article abstract of DOI:10.1016/j.tetlet.2016.04.062

Bis-2,5-dimethylene-2,5-dihydrothiophenes have been generated in the gas-phase by flash vacuum pyrolysis (FVP) of diester precursors. These thiophene-based bis-(p-quinodimethanes) are shown to undergo reactions leading to macrocycles. The conversions are consistent with a mechanism involving cyclic diradical intermediates followed by disproportionation of the radical centers.

Full text of DOI:10.1016/j.tetlet.2016.04.062

Tetrahedron Letters 57 (2016) 2386–2389
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The chemistry of thiophene-based bis-(p-quinodimethanes): an
approach to macrocycles
Walter S. Trahanovsky a, Douglas A. Klumpp b
a Department of Chemistry and Ames Laboratory, Iowa State University, Ames, IA 50011-3111, United States
b Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL 60115, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Bis-2,5-dimethylene-2,5-dihydrothiophenes have been generated in the gas-phase by flash vacuum
pyrolysis (FVP) of diester precursors. These thiophene-based bis-(p-quinodimethanes) are shown to
undergo reactions leading to macrocycles. The conversions are consistent with a mechanism involving
cyclic diradical intermediates followed by disproportionation of the radical centers.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 4 March 2016
Revised 12 April 2016
Accepted 17 April 2016
Available online 22 April 2016
Keywords:
para-Quinodimethane
Pyrolysis
Diradical
Macrocycle
Thiophene
Introduction
reactive intermediates shown to form oligomers and polymers in
solution. The heterocycle-based p-quinodimethanes are conve-
p-Quinodimethanes are an important class of organic reactive
intermediates, first proposed by Szwarc in a report describing the
pyrolysis of p-xylene.1 Based on the observed pyrolysis products,
the parent p-quinodimethane (p-xylylene, 1) was suggested as
the key reactive intermediate. p-Xylylene (1) and various deriva-
tives have been studied extensively since Szwarc’s initial report,
in part due to the commercial importance of poly-p-xylylene
macromolecules.2,3 Their unique electronic properties have also
been the subject of many theoretical investigations.4 A variety of
methods have been used to generate p-xylylene (1)5 and it has also
been characterized by spectroscopic methods.6
niently generated by flash vacuum pyrolysis of the corresponding
heterocyclic ester. For example, the thiophene-based p-quin-
odimethane (3) is formed by elimination of benzoic acid from ester
4 (Scheme 1).7b The observation of cyclophane products (i.e., 5 and
6) is consistent with the formation of diradical intermediates.
Some time ago, we described the generation of bis(furan-based)
p-quinodimethanes (8) by the pyrolysis of diester substrates (7).8
The bis(furan-based) p-quinodimethanes were found to give prod-
ucts consistent with diradical chemistry, including products from
disproportionation, cleavage, and coupling reactions. The chem-
istry also gives macrocyclic products from 15 to 22 carbons in fair
yields (23–58%) from the bis(furan-based) p-quinodimethanes.
Both compounds 2 and 3 are well known heterocycle-based p-
quinodimethanes. These heterocyclic systems have been generated
by a variety of methods7 and both the furan- and thiophene-based
p-quinodimethanes (2 and 3) have been characterized by spectro-
scopic methods. Like the p-xylylene (1), compounds 2 and 3 are
Based on these results, we have sought to extend the chemistry
to bis(thiophene-based) p-quinodimethanes. As described below,
convenient methods have been developed for the synthesis of the
precursor thiophene diesters. Flash vacuum pyrolysis of the thio-
phene diesters has provided macrocycles in fair yields. These
pyrolysis products have been further transformed to cyclopentade-
cane and trace quantities, the natural product DL-muscone.
E-mail addresses: wstrahan@isu.edu (W.S. Trahanovsky), dklumpp@niu.edu
(D.A. Klumpp)
http://dx.doi.org/10.1016/j.tetlet.2016.04.062
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

W. S. Trahanovsky, D. A. Klumpp / Tetrahedron Letters 57 (2016) 2386–2389
2387
The pyrolysis experiments were done using previously
described methods.6a Briefly, the thiophene substrate (100–
500 mg) is placed in
a sample chamber and sublimed (ca.
10ꢀ5 Torr vacuum) through a hot quartz (640 °C) containing
quartz chips. The resulting products exit the pyrolysis tube and
deposit in a liquid nitrogen cooled trap. When all of the substrate
has been sublimed, chloroform is distilled into the trap and the
products are isolated. The pyrolysis gives two equivalents of
acetic acid, so anhydrous sodium carbonate is added to the trap.
The solution is then filtered and the product mixture is subjected
to analysis and product purification.
When compound 10 is subject to FVP, three products are
observed. Like the analogous furan-based system, the thiophene
diester (10) provides a 15-carbon macrocycle (15) as the major
product in 45% yield (Scheme 3). NMR analysis indicates that the
olefin is formed with cis stereochemistry. Another significant pro-
duct is the acyclic aldehyde 16, isolated in 21% yield. The yield of
this product (16) varies somewhat between experiments, however.
Analysis of the crude pyrolysate also shows the presence of a minor
amount of the thiophene-based p-quinodimethane (3). Within
24 h, the presence of 3 is negligible. A good NMR spectrum of 3
is obtained by spectral subtraction of the crude product mixture
NMR spectrum from immediately after pyrolysis and the spectrum
from 24 h later. With 1H NMR peaks at d 6.5, 5.3, and 5.0, there is a
good match with the published spectrum of the thiophene-based
p-quinodimethane (3).11 Presumably, this reactive thiophene-
based p-quinodimethane undergoes its known oligomerization
reactions. None of the expected products from 3 could be isolated,
however.
When the ketone 13 and alcohol 14 derivatives are subject to
pyrolysis, the expected macrocyclic products are formed. In the
case of substrate 13, the enone 17 is formed as the major product,
but the vinyl-substituted product 18 is also formed in considerable
amount. Both products are consistent with the formation of the
thiophene-based bis-(p-quinodimethanes), vide infra. The alcohol
14 likewise gives the macrocyclic alcohol (19) from pyrolysis
(Scheme 4).
Scheme 1. Chemistry of the thiophene-based para-quinodimethane (3).
Results
Our initial goal was the preparation of a thiophene diester hav-
ing a saturated hydrocarbon chain. This was accomplished readily
through the well-known nucleophilic chemistry of the 2-thienyl
anion (Scheme 2).9 Thus, thiophene provides the bis-(2-thienyl)
pentane (8) from 1,5-dibromopentane in 52% isolated yield. Subse-
quent formylation gives the dialdehyde (9, 93% yield). Reduction
and acylation (97%, two steps) then provides the desired thiophene
diester (10).
In addition to the saturated carbon tether of 10, thiophene die-
sters were prepared with a carbonyl and hydroxyl groups in the
bridging chain. Starting from the readily prepared dienone (11),10
both the ketone (13) and alcohol (14) are prepared. The syntheses
first involve catalytic hydrogenation of the olefinic bonds to give
the 3-pentanone derivative (12, Eq. 1). Derivative 13 is prepared
by protection of the carbonyl group of 12 as the 1,3-dioxolane
and subsequent formylation/reduction/acylation with a deprotec-
tion step (see Supporting information). Alcohol 14 is prepared by
initial reduction of the carbonyl group of 12 and protection as
the tert-butyldimethylsilyl ether and subsequent formylation/
reduction/acylation with a deprotection step.
The observed products are consistent with the formation of bis
(thiophene-based) p-quinodimethanes. Thus, compounds 10 and
14 undergo pyrolysis to give the bis(thiophene-based) p-quin-
odimethanes 19–20 and two equivalents of acetic acid (Scheme 5).
As described previously, these elimination reactions occur through
a series of steps.7b The acetate group migrates across the thiophene
ring by two symmetry allowed [3,3] sigmatropic bond migrations.
This places the acetate in position to undergo the b-elimination of
acetic acid—generating the thiophene-based p-quinodimethane
unit. Alternatively, pseudopericyclic rearrangements and ester
eliminations have been suggested for similar reactions.12 With for-
mation of the bis(thiophene-based) p-quinodimethanes (20),
cyclization leads to diradical intermediates 21–22. This
Scheme 2. Synthesis of pyrolysis substrate.
ð1Þ
Scheme 3. Pyrolysis products from diester 10.

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W. S. Trahanovsky, D. A. Klumpp / Tetrahedron Letters 57 (2016) 2386–2389
Scheme 6. Proposed mechanism for the formation of side-products 3 and 16.
Scheme 4. Pyrolysis products from diesters 13 and 14.
intramolecular reaction is similar to the proposed dimerization of
the thiophene-based p-quinodimethane 3 and formation of the
diradical (Scheme 1). The cyclic diradicals 21–22 then undergo
hydrogen atom transfer to provide the final olefin products 15
and 18. In these systems, the ring-fused [2,2]-cyclophanes—radical
coupling products from 21 and 22—were not detected. In total, the
transformation of the thiophene diesters to the macrocycle prod-
ucts requires eight independent reaction steps. NMR analysis of
the crude product mixtures did not show the presence of any of
the bis(thiophene-based) p-quinodimethanes—suggesting the
entire cyclization occurs in the gas-phase during pyrolysis.
Scheme 7. Proposed mechanism for the formation of side-products 17 and 18.
leads to the diradical 26. The observed products are thought to
arise from two competing reaction paths. As in the previous sys-
tems, hydrogen atom migration (route a) gives macrocyclic enone
(17). Extrusion of carbon monoxide (route b) from the 1,5-diradical
leads to formation of the two vinyl groups in product 18. Unfortu-
nately, this latter process is somewhat favorable at the high tem-
peratures of pyrolysis and it limits the yield of the enone product
(17, 35% yield).
In the pyrolysis of thiophene diester 10, two acyclic products
were observed. The acyclic aldehyde (16) was isolated and a low
concentration of the thiophene-based p-quinodimethane 3 was
detected by NMR. It is unlikely that these products are formed
from the bis(thiophene-based) p-quinodimethane 19. It is pro-
posed these by-products are formed by bond homolysis and subse-
quent reaction steps (Scheme 6). Thus, cleavage of the CAO bond
gives radical 23 and an acetoxy radical (or methyl radical and
CO2). Radical 23 can provide a route to both minor products: ben-
zylic CAC bond cleavage gives intermediate 3 and compound 16 is
formed by hydrogen atom shift and cleavage of the acetate group.
In the pyrolysis of diester 13, products 17 and 18 are formed
and both compounds may explained by the involvement of a bis
(thiophene-based) p-quinodimethane and subsequent diradical
intermediate (Scheme 7). Elimination of the acetic acid provides
the bis(thiophene-based) p-quinodimethane (25) and ring-closure
The above pyrolysis reactions provide novel thiophene-contain-
ing 15-carbon macrocycles. Thiophene rings may be removed by
treatment with Raney-nickel,13 providing a potential route to sat-
urated macrocycles. Thus, compound 15 is treated with Raney-
nickel in ethanol and cyclopentadecane (27) is formed in good
yield (Scheme 8). Enone 17 reacts with methyl cuprate to provide
compound 28. Subsequent reduction with Raney-nickel gives dl-
muscone (29).14 However only trace quantities of the natural pro-
duct could be prepared—identified by GCMS spectral match—due
to the low recovery of the previous steps.
Conclusions
In summary, we have prepared macrocyclic products in
fair yields by flash vacuum pyrolysis of thiophene diesters. A
Scheme 5. Proposed mechanism for the formation of macrocycles 15 and 18.
Scheme 8. Conversion to cyclopentadecane (27) and DL-muscone 29.

W. S. Trahanovsky, D. A. Klumpp / Tetrahedron Letters 57 (2016) 2386–2389
2389
Schwalm, T.; Wiesecke, J.; Immel, S.; Rehahn, M. Macromolecules 2007, 40,
8842.
mechanism is proposed involving formation of bis(thiophene-
based) p-quinodimethanes in the gas-phase and cyclization to
diradical intermediates. A disproportionation of the radical centers
provides the observed macrocycles. In combination with nickel-
catalyzed reduction, the chemistry represents a novel method for
preparing large, saturated carbocycles.
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Acknowledgments
This work was supported in part by the U.S. Department of
Energy, Office of Basic Energy Sciences, Division of Chemical
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Supplementary data
Supplementary data (experimental procedures and characteri-
zation data for new compounds) associated with this article can
be found, in the online version, at http://dx.doi.org/10.1016/j.tet-
let.2016.04.062.
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