Arynes as Radical Acceptors: TEMPO-Mediated Cascades Comprising Addition, Cyclization, and Trapping

Article abstract of DOI:10.1002/anie.202012654

The application of arynes as radical acceptors is described. The stable radical TEMPO (2,2,6,6-tetramethyl piperidine 1-oxyl) is shown to add to various ortho-substituted benzynes generating the corresponding aryl radicals which engage in 5-exo or 6-endo cyclizations. The cyclized radicals are eventually trapped by TEMPO. The introduced method provides ready access to various dihydrobenzofurans, oxindoles, and sultones by a conceptually novel approach.

Full text of DOI:10.1002/anie.202012654

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Accepted Article
Title: Arynes as Radical Acceptors: TEMPO-mediated Cascades
Comprising Addition, Cyclization and Trapping
Authors: Maximilian Scherübl, Constantin G. Daniliuc, and Armido
Studer
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202012654
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Arynes as Radical Acceptors: TEMPO-mediated Cascades
Comprising Addition, Cyclization and Trapping
Maximilian Scherübl, Constantin G. Daniliuc, and Armido Studer*
[a]
M. Scherübl, C. G. Daniliuc, Prof. Dr. A. Studer
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität
Corrensstraße 40, 48149 Mꢀnster (Germany)
E-mail: studer@uni-muenster.de
Supporting information for this article is given via a link at the end of the document
Abstract: The application of arynes as radical acceptors is described.
The stable radical TEMPO (2,2,6,6-tetramethyl piperidine 1-oxyl) is
shown to add to various ortho-substituted benzynes generating the
corresponding aryl radicals which engage in 5-exo or 6-endo
cyclizations. The cyclized radicals are eventually trapped by TEMPO.
The introduced method provides ready access to various
dihydrobenzofurans, oxindoles and sultones via a conceptually novel
approach.
acceptors exploiting their biradical character have not been
reported to date.
Arynes are an interesting class of reactive intermediates which
can be used as versatile building blocks in organic chemistry, as
convincingly documented by their application in natural product
synthesis.[1] Structurally, arynes exhibit in the ground state a
strained triple bond with a large singlet-triplet gap (37.7 kcal mol−1
for benzyne).[2] A direct consequence of this unusual bent alkyne
structure is their low-lying LUMO which renders arynes highly
reactive.[1c,3] The electrophilic character of arynes has been
intensively studied and multi-component[4], aryne relay[5] and -
bond insertion[6] reactions have been developed (Scheme 1A).
Furthermore, the aryne triple bond engages in pericyclic reactions
which has been exploited in [2+2] and [4+2] cycloadditions
(Scheme 1B).[7] Arynes have also found use as intermediates in
transition-metal-catalyzed
[2+2+2]
reactions[8],
-bond
insertions[9], C−H activations[10] and multicomponent reactions[11]
(Scheme 1C). For example, in the presence of a Pd-catalyst,
benzyne undergoes a cyclotrimerization to give triphenylene.[8a]
The low-lying LUMO of arynes should also make them ideal
radical acceptors; however, cascades comprising arynes as
acceptors are nearly unexplored.[12] The main challenge in such
transformations lies in the low concentrations of both aryne and
radical, as both reaction components are highly reactive
intermediates.[13] Therefore, coupling of a radical with an aryne in
a chain reaction is highly challenging and not surprisingly only
very few aryne radical reactions have been reported, mostly
discovered as unexpected processes. For example, Shioji and
coworkers found that benzyne reacts with sterically highly
congested thiones not via the targeted [2+2] cycloaddition but as
a biradical adding to the C-S double bond.[12c] Wang and
coworkers[12h] isolated dibenzoselenophenes by reacting
tetraynes generated in a hexadehydro Diels-Alder process with
diphenyldiselenide. They suggested a mechanism based on a
free radical reaction. Murphy and Tuttle showed that benzyne can
act as a radical initiator in base promoted homolytic aromatic
substitutions.[12g] However, to the best of our knowledge,
preparative valuable radical cascades comprising arynes as
Scheme 1. Arynes as reactive intermediates in synthesis (TEMPO = 2,2,6,6-
tetramethyl piperidine 1-oxyl, TMP = (2,2,6,6-tetramethyl)-piperidin-1-yl).
We envisioned to address the critical “concentration problem” of
aryne radical chemistry by using nitroxides that are stable and
persistent radicals as the aryne reaction partners.[13b,14] To our
knowledge, reactions of arynes with nitroxides have not been
reported to date. Our strategy is depicted in Scheme 1D. An in
situ generated aryne of type A bearing a pendant second radical
acceptor should react with TEMPO, added as a stable reagent, to
the aryl radical B. This in turn will undergo a fast 5-exo-cyclization
to the corresponding cyclized alkyl radical, which will be finally
trapped by a second equivalent of TEMPO to give the trapping
1
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product 1. This unique transformation, comprising three
consecutive -bond formations, deserves further comments:
Since TEMPO addition to an unactivated alkene is not an efficient
reaction,[15] we expect highly chemoselective initial addition of
TEMPO to the highly reactive aryne functionality in A. Moreover,
due to the bulkiness of TEMPO, addition onto the aryne should
occur with high regioselectivity.[16] The subsequent 5-exo-
cyclization should be faster than direct intermolecular TEMPO
trapping of B and the terminating radical/radical cross coupling of
the cyclized radical with the second TEMPO should be selective
due to the high relative concentration of the persistent TEMPO
radical.[13b]
albeit lower yields were noted in these cases (30%, 53%, entry 10
and 11).
Table 1. Reaction optimization.[a]
To evaluate the feasibility of such an unprecedented cascade, we
first investigated the reactivity of benzyne towards TEMPO.
TEMPO is a cheap, commercially available and bench-stable
nitroxyl radical which has been used as a radical trapping reagent,
in living radical polymerizations and in oxidations of alcohols in
combination with stoichiometric amounts of a cooxidant.[17] The
Kobayashi method was selected for aryne generation.[18,19,20]
Pleasingly, we found that the reaction of the triflate 2 with CsF
(3.0 equiv) and 18-crown-6-ether (3.0 equiv) in the presence of
TEMPO (5.0 equiv) in n-hexane provided the TEMPO-bisadduct
3 in 48% yield, clearly documenting that TEMPO addition onto an
aryne is occurring (Scheme 2). Product 3 is formed by the
trapping of the intermediately generated TEMPO adduct aryl
Entry
1[b]
2[c]
3[b]
4[b]
5[b]
6
TEMPO
5 equiv
2 equiv
10 equiv
5 equiv
5 equiv
5 equiv
5 equiv
5 equiv
5 equiv
5 equiv
5 equiv
Solvent
n-hexane
n-hexane
n-hexane
n-hexane
PhMe
Temperature
Yield 1a
59%
35%
57%
59%
60%
58%
50%
56%
34%
30%
53%
rt
rt
rt
0 °C
0 °C
rt
MeCN
7
MeCN
0 °C
−20 °C
rt
radical with
bisalkoxyamine 3 was found to be moderately stable and its
structure was unambiguously confirmed by X-ray
crystallography.[21]
a
second equivalent of TEMPO. Notably,
8
MeCN
9
1,2 DCE
MeCN
10[d]
11[e]
70 °C
rt
MeCN
[a]Reaction conditions: 4a (0.1 mmol, 1.0 equiv), TEMPO (0.5 mmol, 5.0 equiv),
CsF (0.3 mmol, 3.0 equiv) and solvent (1 mL, 0.1 M). Yields represent isolated
yields. [b]18-crown-6 ether (0.3 mmol, 3.0 equiv) was added. [c]CsF (0.2 mmol,
2.0 equiv) and 18-crown-6 ether (0.2 mmol, 2.0 equiv) were used. [d]K2CO3
(0.40 mmol, 4.0 equiv) and 18-crown-6 ether (0.40 mmol, 4.0 equiv) were used
to prepare the aryne. [e]Tetrabutylammonium difluorotriphenylsilicate (TBAT,
0.30 mmol, 3.0 equiv) was used to prepare the aryne. rt = room temperature.
With optimized conditions in hand (Table 1, entry 1), we tested
different triflates 4b-n in this novel cascade (Scheme 3). For the
preparation of the starting materials, we refer to the Supporting
Information (SI). A substituent at the 5-position of the intermediate
3-allyoxy aryne is tolerated: Electron-donating groups such as
phenyl- (1b) and methoxy (1c) led to lower yields, whereas the
electron-withdrawing chloro-substituent showed little effect on the
yield (1d). In the NMR spectra of products 1b to 1d an inseparable
side product was identified in each case (3-9%, see SI). These
side products derive from a 1,6-HAT from the TEMPO-methyl
group of the intermediate aryl radical B with subsequent TEMPO
trapping (see analogous compound 6e in Scheme 4 below).
Moreover, the generally moderate yields observed are also
caused by the instability of the products (labile N−O bond in aryl-
TEMPO alkoxyamines).
The allyloxy group can be further substituted (R2-group) by an
ester (1e), acetyl (1f) or methyl group (1i) providing the
corresponding dihydrobenzofurans in 38-58% yields[22] with
moderate diastereoselectivities for the TEMPO trapping step (3:1
to 5:1). The structure of the major isomer of ester 1e was
confirmed by X-ray crystallography (Figure 1).[21] -Unsaturated
sulfonate esters 4g and 4h gave the targeted sultones 1g and 1h
Scheme 2. Radical reaction of benzyne with TEMPO to give the bisalkoxyamine
3 and crystal structure of 3 (H-atoms are omitted).
Encouraged by this result, we next investigated the radical
cascade suggested in Scheme 1D. To this end, triflate 4a was
prepared as the model substrate (Table 1). We were very pleased
to find that upon reacting 4a with CsF (3.0 equiv) and 18-crown-
6-ether (3.0 equiv) in the presence of TEMPO (5.0 equiv) in n-
hexane at room temperature the targeted dihydrobenzofuran 1a
was obtained in 59% yield (entry 1).[22] Decreasing the amount of
TEMPO to 2 equivalents led to a lower yield of 4a, whereas
increasing the TEMPO amount provided a similar yield (35% and
57%, entry 2 and 3). Solvent screening revealed n-hexane,
toluene and acetonitrile to be good solvents for this cascade, but
a worse result was achieved in 1,2-dichloroethane (entry 9). The
good solvents show small differences in the amount of product
formed (entry 4-6). For reactions carried out in n-hexane, 18-
crown-6-ether was required in order to increase the solubility of
the fluoride source. Variation of the temperature (−20 °C to rt)
showed only little impact on the yield (entry 6-8). CsF can be
replaced by TBAT or with K2CO3 at 70 °C for aryne generation,
2
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in 46% and 41% yield, respectively. The sultone 1h was formed
as a diastereomeric mixture (dr = 3:1) and the structure of the
major isomer was unambiguously assigned by X-ray
crystallography (Figure 1).[21]
Figure 1. X-ray crystal structures of the major diastereomers of ester 1e and
sultone 1h. H-atoms are only shown at the stereocenters.
Scheme 3. Radical reaction of o-substituted arynes with TEMPO and
cyclization to bisalkoxyamines. Yields represent isolated yields. Reaction time t
= 1–18 hours. Conditions: [a]Method A: 4 (0.20 mmol, 1.0 equiv), TEMPO
(1.0 mmol, 5.0 equiv), CsF (0.60 mmol, 3.0 equiv), 18-crown-6 ether
(0.60 mmol, 3.0 equiv) and n-hexane (2.0 mL). [b]Method B: 4 (0.20 mmol, 1.0
equiv), TEMPO (1.0 mmol, 1.0 equiv), CsF (0.60 mmol, 3.0 equiv) and MeCN
(2.0 mL). [c]Reaction was performed on 0.25 mmol scale.
By installing an -substituent at the allyloxy group we also
addressed the diastereoselectivity of the fast radical 5-exo-
cyclization. For a tested system (4k), only a moderate selectivity
was noted and the 2,3-disubstituted dihydrobenzofuran 1k was
obtained in 62% yield (dr = 1.5:1). As expected, for -substituted
3-allyloxyarynes, the regioselectivity of the radical cyclization was
not complete. Hence, with the activating ester moiety, a significant
amount of the 6-endo product 1l’ was formed (5-exo:6-endo =
1:1.5). However, the -methyl congener afforded exclusively the
5-exo product 1j. In the NMR spectra of 1j we identified an
inseparable side product that is derived from a 1,6-HAT from the
TEMPO moiety of intermediate B with subsequent TEMPO
trapping. To our surprise, reaction of the acryl amide 4m with
TEMPO under optimized conditions did not afford the expected
bisalkoxyamine, but the oxindole 1m was isolated in 38% yield.
Methacrylamide 4n furnished the quinolinone 1n in 59% yield via
a 6-endo cyclization. In these two cases (1m, 1n), facile TEMPOH
elimination is occurring from the targeted products via an ionic or
a radical pathway.[23]
Scheme 4. Reactions of arynes with TEMPO involving 1,5 or 1,4 HAT to give
bisalkoxyamines 6a-d. Reaction conditions: 5 (0.20 mmol, 1.0 equiv), TEMPO
(1.0 mmol, 5.0 equiv), CsF (0.60 mmol, 3.0 equiv), 18-crown-6 ether
(0.60 mmol, 3.0 equiv) and n-hexane (2.0 mL). [a]Reaction condition: 5e
(1.0 mmol, 1.0 equiv), TEMPO (3.0 mmol, 3.0 equiv), CsF (3.0 mmol, 3.0 equiv)
and MeCN (10 mL). Yields represent isolated yields.
Finally, we investigated the reactivity of the intermediate aryl
radical generated by TEMPO addition to an aryne towards
intramolecular hydrogen atom transfer (HAT), further leveraging
the potential of radical aryne chemistry (Scheme 4). Of note,
radical translocation via 1,5-HAT to aryl radicals has been
successfully used in organic synthesis.[24] The ortho-alkoxyl
substituted aryne precursors 5a-c bearing C−H bond at the -
position of the alkoxyl group engaged in the cascade and the
bisalkoxyamines 6a, 6b and 6c were obtained with similar yields
3
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Niu, P. H. Willoughby, B. P. Woods, Nature 2012, 490, 208-212. d) H.
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(47-54%). These reactions proceed via TEMPO addition to the
intermediate aryne to give the corresponding adduct aryl radical
that further reacts via a 1,5-HAT. The thus generated translocated
alkyl radical is eventually trapped by the second equivalent of
TEMPO to give compounds of type 6. Considering triflate 5c, the
bisalkoxyamine derived from a 1,6-HAT was not identified. In
analogy, triflate 5d reacted via a 1,4-HAT to the mixed acetal 6d
(47%). Surprisingly, subjecting triflate 5e to the standard reaction
conditions did not provide the expected 1,4-HAT derived acetal;
instead, we isolated the 1,6-HAT/TEMPO trapping product 6e
(15%).
In summary, we have shown that arynes react as in situ generated
radical acceptors with the persistent TEMPO radical. The adduct
aryl radical thus generated can then engage in different typical
radical reactions such as direct TEMPO-trapping, cyclization and
intramolecular hydrogen atom transfer. The rearranged radicals
generated in the latter two cases can finally be trapped by the
persistent TEMPO radical in a highly selective radical/radical
cross coupling. In all cases, bisalkoxyamines result in rather good
yields considering the complexity of these cascades. Aryne
radical chemistry nicely complements existing ionic or transition-
metal based reactions of arynes opening new doors in that timely
research area.
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We thank the Deutsche Forschungsgemeinschaft (DFG) for
supporting this project.
Keywords: arynes • radicals • heterocycles • cyclization •
TEMPO
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4
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10.1002/anie.202012654
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Entry for the Table of Contents
Arynes go radical! In situ generated arynes are shown to be good acceptors for the persistent TEMPO radical. The adduct aryl
radicals engage in typical radical reactions such as direct TEMPO-trapping, cyclization or hydrogen atom transfer. Final TEMPO
trapping provides bisalkoxyamines. Considering cyclizations, dihydrobenzofurans, oxindoles and sultones can be prepared via this
conceptually novel aryne chemistry, nicely complementing existing aryne methodology.
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