(5,6-Dihydro-1,4-dithiin-2-yl)methanol as a Versatile Allyl-Cation Equivalent in (3+2) Cycloaddition Reactions

Article abstract of DOI:10.1002/anie.201606411

The title heterocyclic alcohol readily generates a sulfur-substituted allylic cation upon simple treatment with a protic acid, thus facilitating a synthetically useful stepwise (3+2) cycloaddition reaction pathway with a range of conjugated-olefin-type substrates. The introduction of an allyl fragment in this way provided rapid access to a variety of cyclopentanoid scaffolds. The cyclic nature of the cation precursor alcohol was shown to be instrumental for efficient cycloaddition reactions to take place, thus indicating an attractive strategy for controlling the reactivity of heteroatom-substituted allyl cations. The formal cycloaddition reaction is highly regio- and stereoselective and was also used for a short total synthesis of the natural product cuparene in racemic form through a cycloaddition–hydrodesulfurization sequence.

Full text of DOI:10.1002/anie.201606411

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International Edition: DOI: 10.1002/anie.201606411
German Edition: DOI: 10.1002/ange.201606411
Synthetic Methods
(5,6-Dihydro-1,4-dithiin-2-yl)methanol as a Versatile Allyl-Cation
Equivalent in (3+2) Cycloaddition Reactions
Jan Hullaert and Johan M. Winne*
Abstract: The title heterocyclic alcohol readily generates
a sulfur-substituted allylic cation upon simple treatment with
a protic acid, thus facilitating a synthetically useful stepwise
(3+2) cycloaddition reaction pathway with a range of con-
jugated-olefin-type substrates. The introduction of an allyl
fragment in this way provided rapid access to a variety of
cyclopentanoid scaffolds. The cyclic nature of the cation
precursor alcohol was shown to be instrumental for efficient
cycloaddition reactions to take place, thus indicating an
attractive strategy for controlling the reactivity of heteroatom-
substituted allyl cations. The formal cycloaddition reaction is
highly regio- and stereoselective and was also used for a short
total synthesis of the natural product cuparene in racemic form
through a cycloaddition–hydrodesulfurization sequence.
T
he allyl cation is a highly reactive reaction intermediate,
and its archetypical electronic structure is featured prom-
inently in every organic-chemistry textbook. Next to simple
addition reactions with various nucleophiles, the allyl
cation—as
a two-electron three-carbon p-system—also
lends itself to a number of interesting cycloaddition reactions
(Scheme 1a).[1] Because cationic cycloaddition reactions can
in fact proceed by a stepwise ionic mechanism, the typical
limitations dictated by orbital-symmetry factors (Woodward–
Hoffmann rules) do not usually apply to these reactions, thus
giving them very wide scope in terms of possible substrates.
However, cycloaddition reactions of allyl cations have limited
synthetic application, because the resulting initial products
(Scheme 1a, top) are themselves highly reactive carbocation-
ic species that can initiate secondary processes. A reliable
cycloaddition reaction is often made possible by the use of
oxyallyl cations that give stabilized oxonium-ion (or carbonyl-
type) cycloadducts (Scheme 1a, bottom).[1c,d] Synthetic meth-
ods have thus been developed that allow efficient (4+3)[2] and
(3+2)[3] cycloaddition reactions for the rapid elaboration of
cycloheptanoid and cyclopentanoid reaction products, respec-
tively.
Scheme 1. a) Allyl- and oxyallyl-type cations as three-carbon-atom
reagents in cycloaddition reactions. b) Dehydrative cycloheptannula-
tion of oxathiin alcohols through the intramolecular (4+3) cycloaddi-
tion of an oxyallyl-type cation, as reported by Harmata (Ref. [8c]).
c) Dehydrative cyclopentannulation of (5,6-dihydro-1,4-dithiin-2-yl)me-
thanol (reported herein). Tf=trifluoromethanesulfonyl.
precursors that are prone to self-condensation reactions. In
2009, Pattenden and Winne found that furfuryl alcohols act as
quite reliable oxyallyl-type cation precursors in (4+3) cyclo-
addition reactions with conjugated dienes,[4] a reaction that
has now been applied multiple times in the rapid total
synthesis of complex polycyclic natural products and ana-
logues thereof.[5] Moreover, the motif of heteroarene–carbi-
nol reagents in (4+3) cycloaddition reactions has also been
extended to indole-3-carbinols by Wu and co-workers,[6] and
to benzofuran-3-carbinols and benzothiophene-3-carbinols by
Xue, Li, and co-workers.[7]
Encouraged by the success of simple furancarbinols and
indolecarbinols as synthetically useful three-carbon-atom
building blocks,[4–7] we set out to explore different hetero-
cyclic and heteroaromatic alcohols as precursors to stabilized
allyl-type cations that can undergo a similar cycloaddition
reaction. Inspired by the seminal work of Harmata and co-
workers on sulfur-stabilized oxyallyl cations and vinyl thio-
nium ions in cycloaddition reactions,[8] we decided to explore
sulfur-containing heterocycles as possible precursors of reac-
tive allyl-type cations. Harmata reported in a review written
A bottleneck in oxyallyl-cation-type cycloaddition reac-
tions is often the generation of these amphiphilic 1,3-dipolar-
type intermediates that are at the same time highly electro-
philic and nucleophilic, and have to be generated from
[*] J. Hullaert, Prof. Dr. J. M. Winne
Department of Organic and Macromolecular Chemistry
Ghent University
Krijgslaan 281 S4, Gent, 9000 (Belgium)
E-mail: johan.winne@ugent.be
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201606411.
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in 1997[8c] that the treatment of an oxathiine alcohol with
triflic anhydride (Scheme 1b) afforded the (4+3) cycloadduct
as a 1:1 mixture of cycloadducts in 40% yield. No further
results related to oxathiines have been reported.
In an initial screen of some known hydroxyalkyl-substi-
tuted S-heterocycles with 1,3-cyclohexadiene as a test sub-
strate, non-aromatic (5,6-dihydro-1,4-dithiin-2-yl)methanol
(dhdt-2-methanol, 1) emerged as one of the most promising
heterocyclic reagents, with the clean formation of the
expected cycloadduct 2 in modest yield in the presence of
trifluoroacetic acid (Scheme 2; compare Scheme 1b). The
observed as the major reaction product. Interestingly, the
reaction with 2,5-dimethyl-2,4-hexadiene, which cannot adopt
an s-cis conformation, gave very clean and efficient formation
of the cyclopentanoid adduct 7. When the complex diterpene
natural product abietic acid (8), also containing an s-trans-
locked 1,3-diene moiety, was treated with 1, the pentacyclic
cycloadduct 9 was formed cleanly as a single regio- and
diastereomer and isolated in 60% yield, thus further impli-
cating 1 as a highly useful cyclopentannulation reagent.
To the best of our knowledge, dehydrative heterocyclic-
carbinol (3+2) cycloadditions have so far only been observed
in indolecarbinols by Moody and co-workers,[9a] as well as in
some follow-up studies,[9b,c] including a very recent three-
component reaction reported by Wu and co-workers.[9d]
Furthermore, some benzyl alcohols can undergo similar
reactions that resemble the classical cationic styrene-dimeri-
zation process,[10a] as in the cyclopentannulation of styrenes
with quinone methides or benzyl alcohols, as described by
Angle et al.[10b] Katritzky et al. introduced 2-(benzotriazol-1-
ylmethyl)thiophenes as carbocation precursors in a (3+2)
cycloaddition.[11a] Similarly, Budynina, Trushkov and co-
workers recently reported that some (hetero)aryl cations
generated from donor–acceptor aryl cyclopropanes can
undergo similar (3+2) cycloaddition reactions with alkenes
rather than the expected zwitterion-promoted 1,3-dipolar-
type reactions.[11b] However, these methods either give the
products in low yields or have limited synthetic application
owing to their restricted scope with regard to the substitution
of the allyl-cation fragment. Moreover, in contrast to related
oxyallyl-type cycloaddition reactions, such as those developed
by Kuwajima and co-workers on the basis of 2-(silyloxy)vi-
nylthionium ions,[12] the dhdt-2-methanol reagent 1 enables
the introduction of an unsubstituted allyl fragment (after
hydrodesulfurization; Scheme 1c), which is an option not
offered by most state-of-the-art cycloaddition or cyclopen-
tannulation methods.[13] In fact, dhdt-carbinols such as 1 were
originally developed by Palumbo and co-workers as versatile
allylic alcohol anion equivalents (through alkylation of the
lithiated C3 position).[14]
Scheme 2. Reactions of dhdt-methanol with a range of 1,3-diene
substrates: At À788C, trifluoroacetic acid (2.0 equiv) was added to
1 and the diene (1.2 equiv (product 9), 1.5 equiv (products 3 and 7),
or 3.0 equiv (products 2 and 5)), and the reaction mixture was then
warmed to room temperature.
We further explored the use of 1 as a synthetic equivalent
of an allyl cation for (3+2) cycloaddition reactions. Non-
conjugated alkenes did not afford the corresponding dhdt
cycloadducts in synthetically useful yields, but instead gave
highly complex mixtures of mostly noncyclized (eliminated)
electrophilic alkene adducts (see the Supporting Informa-
tion), as can be expected from the higher reactivity of the
initially formed carbocationic adducts in a stepwise pathway.
Only the reaction of highly substituted 2,3-dimethyl-2-butene
afforded the expected cyclopentene 10 as a major reaction
product (Table 1, entry 1), albeit as a mixture with the
noncyclized alkene 11. However, a wide range of aryl-
conjugated alkenes were found to be viable reaction partners
for the ethanedithiol-tethered allyl cation arising from
alcohol 1, and the expected (3+2) cycloadducts were obtained
in moderate to excellent yields under exceedingly simple,
non-optimized reaction conditions (Table 1, entries 2–13).
The reaction with styrene gave the ethanedithiol-tethered
phenylcyclopentene 12 in reasonable yield (entry 2), although
this polymerization-prone substrate has been reported to be
yield of the (4+3) cycloaddition could be further improved by
switching to more reactive cyclopentadiene. However, in this
case, the expected bridged cycloadduct 3 was isolated
together with a minor side product 4, which seemed to
correspond to the result of a competitive (3+2) cycloaddition.
Despite some effort, we have been unable to achieve
generally efficient intermolecular (4+3) cycloaddition reac-
tions of 1 with a wider range of conjugated dienes, as very
often complex reaction mixtures are obtained, thus pointing
to a much narrower scope than that observed with furan-2-
carbinols.[4b] Nevertheless, we were intrigued to find that with
2,3-dimethyl-1,3-butadiene, a challenging polymerization-
prone diene, the required s-cis-diene conformation of which
is less favored, the cyclopentannulation product 6 was
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Table 1: Reactions of 1 with alkene and styrene-type substrates.[a]
on the phenyl ring (entry 7). The reaction of (E)-b-methyl-
styrene was found to give the trans-cyclopentene 17 stereo-
specifically (Table 1, entry 8). Likewise, the more substituted
E alkenes 18 and 20 gave the trans adducts 19 and 21 as single
regio- and diastereoisomers (entries 9 and 10). Surprisingly,
from a mixture of the alkene isomers (E)- and (Z)-20, the
Z alkene was recovered virtually unchanged from the reac-
tion mixture, and only the trans-adduct 21 was formed. It is
not straightforward to rationalize this kinetic selectivity,
because in a stepwise process both alkenes ((E)- and (Z)-
20) are expected to react via the same initial benzylic cation
intermediate (see Scheme 4b). Under more forcing condi-
tions, the Z alkene was found to give a complex mixture, as
observed with isolated alkene substrates (Table 1, entry 11).
Indeed, the Z alkene 20 can not adopt a fully coplanar
geometry with the phenyl ring, thus further highlighting the
importance of the electronic conjugation in the viable olefin
substrates for this reaction. Finally, tri- and tetrasubstituted
styrene derivatives also gave the expected cycloadducts
(entries 12 and 13), although the sterically encumbered
substrate 23 proved to be quite sluggish, and product 24 was
formed in lower yield (entry 13).
Entry Substrate
1
Product
Yield [%][b]
50 (2:3)
2
3
62
85
4
5
6
83
86
0[c]
7
48
To further establish the scope of the reaction, we also
explored various cyclic alkene substrates. Thus, the phenyl-
hydrindane 25, the benzopentalene 26, the benzofused spiro-
[4.4]nonane scaffold 28, and the aryl spiro[5.4]decane scaffold
29 were all obtained from dhdt-methanol 1 in synthetically
useful yields (Scheme 3). Surprisingly, the reaction of dihy-
8
9
91
95
10
70[d]
11
12
complex
<10
70
13
52
[a] General procedure: A solution of 1 and the aryl alkene (1.5 equiv) in
dichloromethane was cooled to À788C, then treated with trifluoroacetic
acid (2 equiv) and allowed to warm to room temperature over 1–2 h
(total reaction time: 2–10 h). [b] Yield of the isolated product after
chromatography. [c] Substrate 13d was mostly recovered unchanged,
whereas 1 decomposed. [d] Only the trans isomer 21 was formed; 20 was
recovered highly enriched in the Z isomer (Z/E 95:5).
Scheme 3. Cyclopentannulation products derived from 1 and various
cyclic alkenes. [a] Yield after purification by recrystallization to remove
unreacted indole.
very challenging in related cationic reactions.[10b] Additional
alkyl substitution of the alkene bond led to very efficient
annulation reactions, which were also tolerant towards
various substituents on the arene ring (Table 1, entries 3–5).
However, styrene 13d with a strongly electron withdrawing
substituent was found to be completely unreactive with
1 under standard conditions, with 1 just decomposing into
a mixture of various self-condensation products instead
(entry 6). Conversely, a trifluoromethyl group was tolerated
dronaphthalene was extremely sluggish and gave mostly
unreacted starting material in addition to a minor amount of
the expected BCD steroid scaffold 27a. This result can again
be related to a non-coplanar ground-state geometry of the
starting material (as compared to indene). Interestingly, the
introduction of
a cation-stabilizing methyl substituent
restored the cycloaddition reactivity (synthesis of 27b).
Finally, inspired by the dearomative (3+2) cycloaddition
reactions developed by Wu and co-workers between indoles
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and classical oxyallyl cations,[15] we found that also 2,3-
disubstituted indoles could serve as viable substrates in this
cyclopentannulation reaction (see product 30).
Remarkably, when we investigated noncyclic analogues of
dhdt-2-methanol, such as 31 (Scheme 4a), we no longer
Scheme 5. Total synthesis of (Æ)-cuparene (33) from 1 and 23 in three
steps.
amount of the dhdt-methanol reagent 1 (1.5 equiv) was added
over a prolonged period at room temperature, the desired
cycloadduct 24 was isolated in 92% yield.
In conclusion, the scope of (oxy)allyl-type all-carbon
(3+2) cycloaddition reactions has been expanded with
a highly versatile, bench-stable reagent that enables the
simple introduction of an allyl fragment to a considerable
range of olefin reaction partners, thus providing access to
a variety of polycyclic scaffolds in a single step. We have
further demonstrated the utility of this approach by the
straightforward total synthesis of a cyclopentanoid natural
product. The process is also mechanistically intriguing, as the
cyclic nature of the dhdt reagent seems to be crucial to the
success of the cycloaddition reaction. This allylic-cation
“tethering” may thus be an interesting strategy to further
develop carbocationic reactions. In ongoing studies, we are
investigating the details of the reaction mechanism of this
cycloaddition and exploring the synthetic potential of dhdt-
carbinol derivatives.
Scheme 4. a) Markedly different reactivity of a noncyclic analogue 31
of the dhdt-methanol reagent 1. b) Mechanistic possibilities for the
(3+2) cycloaddition.
observed cycloaddition reactions under standard conditions
with a range of substrates (see the Supporting Information).
After the complete conversion of 31, no major reaction
product was detected, besides the mostly unreacted styrene-
type starting material. Some minor uncyclized addition
products were observed, as well as a complex mixture of
degradation products of 31, thus indicating self-condensation
reactions of this alcohol that quench the initially generated
electrophilic cation before electrophilic addition to the
olefinic substrate can take place (see Scheme 4b). This
observation indicates that the cyclic nature of the dhdt-
carbinol reagent is crucial. It is not fully clear at this time why
the ring is so important, but the restricted rotational freedom
of 1, as well as the related enforced conjugation of the sulfur
lone pair, may block certain undesired cationic reaction
pathways and promote others. Furthermore, the reaction of
1 with linear vinyl thioethers, suitable substrates for some
oxyallyl-type cations,[12] also resulted in alkylthio-transfer
pathways (see the Supporting Information). Our observations
with substrates such as 31 confirm previous reports that in
contrast to alkoxyallyl cations, the corresponding alkylth-
ioallyl cations show no useful cycloaddition reactivity,[1b] thus
further highlighting the unique reactivity of dhdt-methanol 1.
As a final demonstration of the synthetic utility of dhdt-2-
methanol (1), we completed a short total synthesis of the
natural bicyclic sesquiterpene cuparene (33) in racemic form
(Scheme 5).[16] Hydrodesulfurization and subsequent hydro-
genation of the cycloadduct 24 obtained from 1 and the
alkene 23 afforded this natural product with two contiguous
quaternary centers in just three synthetic operations. The
challenging tetrasubstituted alkene substrate 23 was con-
verted into 24 in only moderate yield under the standard
reaction conditions (Table 1, entry 13), but when an excess
Acknowledgements
We thank Bram Denoo for assistance with initial screening
studies, and Dr. Davy Sinnaeve for help in the interpretation
1
of the H NMR spectrum of 19. J.H. thanks the Agency for
Innovation by Science and Technology in Flanders (IWT) for
a doctoral grant (Hermes Fonds). J.M.W. thanks the Research
Foundation–Flanders (FWO) for providing
expense grant (KAN).
a research
Keywords: allyl cations · cycloaddition · cyclopentanoids ·
fused-ring systems · thionium ions
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Received: July 1, 2016
Revised: August 12, 2016
Published online: && &&, &&&&
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Communications
Synthetic Methods
Locked and loaded: Ethanedithiol was
used as a temporary tether to control the
reactivity of the allyl cation. A thionium-
stabilized carbocation was thus gener-
ated from allyl alcohol under acidic con-
ditions and directly used in a stepwise
(3+2) cycloaddition with a range of
alkene substrates to give a variety of
cyclopentanoid products (see scheme). A
short total synthesis of the natural prod-
uct cuparene in racemic form is also
described.
J. Hullaert, J. M. Winne*
&&&& — &&&&
(5,6-Dihydro-1,4-dithiin-2-yl)methanol as
a Versatile Allyl-Cation Equivalent in
(3+2) Cycloaddition Reactions
6
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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