A Bulky Thiyl-Radical Catalyst for the [3+2] Cyclization of N-Tosyl Vinylaziridines and Alkenes

Article abstract of DOI:10.1002/anie.201602723

Thiyl-radical-catalyzed cyclization reactions of N-tosyl vinylaziridines and alkenes were developed as a new synthetic method for the generation of substituted pyrrolidines. The key to making this process accessible to a broad range of substrates is the use of a sterically demanding thiyl radical, which prevents the undesired degradation of the catalyst.

Full text of DOI:10.1002/anie.201602723

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201602723
German Edition: DOI: 10.1002/ange.201602723
Radical Reactions
A Bulky Thiyl-Radical Catalyst for the [3+2] Cyclization of N-Tosyl
Vinylaziridines and Alkenes
Takuya Hashimoto, Kohei Takino, Kazuki Hato, and Keiji Maruoka*
Abstract: Thiyl-radical-catalyzed cyclization reactions of
N-tosyl vinylaziridines and alkenes were developed as a new
synthetic method for the generation of substituted pyrrolidines.
The key to making this process accessible to a broad range of
substrates is the use of a sterically demanding thiyl radical,
which prevents the undesired degradation of the catalyst.
[3+2] cyclization reactions catalyzed by an achiral thiyl
radical were introduced as early as 1988,[8] the corresponding
“round-trip” thiyl-radical catalysis has not been investigated
further, although it would provide access to other synthetic
methodologies.[9]
Herein, we report the use of this unexplored thiyl-radical
catalysis for the [3+2] cyclization of N-tosyl vinylaziridines
with a variety of alkenes as a new synthetic pathway to
substituted pyrrolidines (Scheme 1b).[10] This seemingly facile
reaction is severely hampered by catalyst degradation;
however, this obstacle may be circumvented by the design
of a sterically demanding thiyl-radical catalyst. Although
transition-metal- and Lewis acid catalyzed [3+2] cyclization
reactions of vinylaziridines and alkenes have already been
reported,[11,12] these reactions are restricted to electron-
deficient alkenes. Owing to the polarity-reversal nature of
the thiyl-radical catalysis, our method offers an electronically
reversed sense of reactivity, thus favoring electron-rich alkene
substrates.[13]
Organic thiyl radicals possess the unique ability to catalyze
radical reactions.[1,2] In nature, such thiyl-radical-mediated
catalytic reactions are indispensable for the biosynthesis of,
for example, deoxyribonucleotides from ribonucleotides.[3]
The synthetic utility of thiyl-radical catalysis also reaches
into organic chemistry, and has led to the development of
polarity-reversal catalysis.[4,5] Recently, interest in thiyl-radi-
cal catalysis has been rekindled, as these radicals may serve as
a hydrogen-transfer cocatalyst in photoredox catalysis.[6]
However, despite these remarkable examples, the number
of organic reactions catalyzed by thiyl radicals still remains
very limited, in sharp contrast to the rich diversity of other
homogeneous catalytic reactions. In homogeneous catalysis,
judicious catalyst design is crucial, as it enables the selectivity
and/or reaction yield to be improved relative to that observed
with the unmodified catalyst. We envisaged that the applica-
tion of this fundamental strategy to thiyl-radical catalysis
should greatly expand its utility in organic synthesis. In this
context, we recently developed a chiral organic thiyl radical
for the [3+2] cyclization of vinylcyclopropanes and electron-
rich alkenes; this reaction afforded cyclopentanes with high
enantioselectivity (Scheme 1a).[7] Although conventional
As the reaction proceeds through the addition of an
electron-deficient N-tosylaminyl radical to the alkene, we
initially examined the reaction of N-tosyl vinylaziridine (1)
with electron-rich tert-butyl vinyl ether (Scheme 2; for
Scheme 2. Preliminary experiments.
a plausible mechanism, see Scheme 3). The catalytically
active thiyl radical was generated photolytically from the
corresponding aryl disulfide. After the screening of some
readily available disulfides (catalyst loading: 5 mol%), we
found that the use of electron-deficient pentafluorophenyl
disulfide afforded 2a in modest yield (74%). However, we
soon realized that this thiyl-radical-catalyzed [3+2] cycliza-
tion suffers from poor reactivity towards less reactive alkenes.
A representative example is the reaction with styrene, which
gave the corresponding product 2b in low yield (23%).
Unfortunately, the yield could not be increased even by
prolonging the reaction time, and higher catalyst loadings
only led to a proportional increase in the yield, thus indicating
deactivation of the catalyst.[14]
Scheme 1. Thiyl-radical-catalyzed [3+2] cyclization reactions.
[*] Dr. T. Hashimoto, K. Takino, K. Hato, Prof. Dr. K. Maruoka
Department of Chemistry, Graduate School of Science
Kyoto University
Sakyo, Kyoto, 606-8502 (Japan)
This radical cyclization starts with the attack of a thiyl
radical on vinylaziridine 1 to generate aminyl radical I
(Scheme 3). In the productive catalytic cycle, this radical
E-mail: maruoka@kuchem.kyoto-u.ac.jp
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201602723.
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Table 1: Optimization of the reaction conditions.[a]
Entry
(ArS)2
Yield [%][b]
d.r.[c]
1
2
3
4
5
6
5a
5b
5c
5d
6a
6b
6c
6c
10
13
48
7
80
71
88
87
67:33
72:28
69:31
64:36
72:28
72:28
72:28
72:28
7
8[d,e]
[a] Reaction conditions: N-tosyl vinylaziridine (1, 0.10 mmol), styrene
(0.12 mmol), disulfide (0.005 mmol). [b] Combined yield of the diaste-
reomers, as determined by 1H NMR spectroscopy with mesitylene as an
internal standard. [c] The diastereomeric ratio (trans/cis) was determined
by 1H NMR analysis of the crude material. [d] The reaction was carried
out for 2 h with 6 mol% of the disulfide. [e] Isolated yield.
Scheme 3. Proposed catalytic cycle and catalyst-decomposition path-
ways.
species reacts with an alkene to afford carbon radical II,
which cyclizes to furnish 2 with concomitant regeneration of
the thiyl radical. To elucidate the cause of catalyst deactiva-
tion, we scrutinized the residual products of the reactions
described above. The isolation and identification of minor by-
products revealed that the catalyst was trapped mainly by two
different pathways. One decomposition pathway for the
catalyst is the abstraction of a hydrogen atom from the
intermediate aminyl radical I to give allylic sulfide 3. Another
is the formation of bis(arylthiolated) 4, which is formed by the
addition of the thiyl radical to the alkene, followed by
a reaction of the thus generated carbon radical III with
another thiyl radical or the disulfide.[15] Whereas the former
pathway (I!3) is hard to circumvent, we reasoned that the
latter pathway leading to 4 could be prevented by appropriate
catalyst design.
vinylaziridine 1, the catalyst loading was slightly increased to
6 mol%. Under these optimized reaction conditions, the
reaction afforded the desired pyrrolidine in 87% yield within
2 h (entry 8). Although the reaction proceeds in a variety of
solvents, benzene was chosen for this study because of the
high solubility of the catalyst therein and the low probability
of undesired hydrogen abstraction from the solvent.
We examined the scope of the reaction by subjecting
a variety of styrene derivatives to the optimized reaction
conditions (Scheme 4).[16] Even though we observed that the
position of the functional group on the aryl moiety did not
affect the reaction yield (products 2c,d), the electronic
features of the styrenes were found to have a substantial
effect on their reactivity. Whereas the cyclization with
electron-rich styrene derivatives reached completion within
2 h (products 2e,f), the reaction of electron-deficient alkenes,
such as 4-bromostyrene, required longer reaction times and/
or higher catalyst loadings (products 2h–j). The catalytic
system was applicable to a-substituted styrenes, which
afforded the corresponding pyrrolidines with a quaternary
center in good yield and with modest diastereoselectivity
(products 2k–m). The use of a-silyloxy and a-alkoxy styrenes
enabled the incorporation of a protected tertiary alcohol
moiety in the pyrrolidine ring (products 2n,o). The reactivity
of these electron-rich styrenes was found to be higher than
that of a-alkyl styrenes. Notably, the reaction also proceeded
with a b-substituted styrene to give the corresponding
trisubstituted pyrrolidine 2p. A trans configuration was
ascertained for the stereochemical relationship between the
methyl and phenyl group of 2p; thus, a mixture of just two out
of four possible diastereomers was obtained. The E/Z
isomerization of b-methylstyrene is faster than the reaction
under the previously described optimal reaction conditions,
thus justifying the use of isomeric mixtures.
We envisaged that the use of a sterically hindered thiyl
radical should prevent the second addition of a thiyl radical or
disulfide (pathway III!4), thereby making the thiyl radical
available for the catalytic cycle. To validate this hypothesis,
we screened several aryl disulfides. For example, the 2,6-
dimethylphenyl and 2,4,6-triisopropylphenyl disulfides 5a
and 5b generated pyrrolidine 2b merely in low yields
(Table 1, entries 1 and 2), and the use of electron-deficient
tris(trifluoromethyl)phenyl disulfide 5c promoted the reac-
tion only modestly (entry 3). No improvement in conversion
was observed when 2,6-diarylphenyl disulfides, such as 2,6-
dimesitylphenyl disulfide 5d, were used (Table 1, entry 4).
Consequently, we focused our attention on the introduction of
sterically more demanding silyl groups at the 2,6-positions of
the aryl disulfide. Even though the use of trialkylsilyl-
substituted catalysts led to merely modest conversion at
best (data not shown), the introduction of triphenylsilyl
groups (disulfide 6a) resulted in a dramatic improvement in
the yield to 80% (Table 1, entry 5). To further improve the
catalytic activity, we fine-tuned the electronic properties of
the 2,6-bis(triphenylsilyl)aryl disulfide 6 by replacing the
substituent at the para position of the catalyst (Table 1,
entries 5–7). These experiments provided us with the optimal
catalyst 6c, which contains triphenylsilyl groups at the ortho
positions and a trifluoromethyl group at the para position of
the principal aryl moiety. To secure full consumption of
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Scheme 4. Substrate scope with respect to the styrene derivative. Reaction conditions: N-tosyl vinylaziridine 1 (0.10 mmol), alkene (0.12 mmol),
disulfide (0.06 mmol), 2–24 h. The combined yield of the diastereomeric products is given in each case. Diastereomeric ratios (trans/cis) were
1
determined by H NMR analysis of the crude material. The structure of the major diastereomer is shown. [a] Disulfide: 10 mol%. [b] Alkene:
5 equivalents. [c] Disulfide: 2 mol%. [d] Disulfide: 3 mol%. [e] Alkene: 20 equivalents. Boc=N-butoxycarbonyl, Ns=2-nitrobenzenesulfonyl,
TMS=trimethylsilyl, TIPS=triisopropylsilyl.
Subsequently, we focused our attention on the use of other
alkenes (Scheme 4, products 2a and 2q–x). Monosubstituted
electron-rich alkenes containing a vinyl ether, silyl enol ether,
or enamide moiety reacted smoothly to afford the hetero-
functionalized pyrrolidines 2a, 2q, and 2r, respectively. The
cyclization with a vinyl ether or a vinyl amide was possible
with a catalyst loading of 2 and 3 mol%, respectively.
Aliphatic 1,1-disubstituted alkenes could also be successfully
converted, as demonstrated by the incorporation of exome-
thylenecyclohexane and b-pinene moieties to give spiropyr-
rolidines 2s and 2t. The reaction with pinene proceeded
exclusively on the sterically less hindered face of the alkene.
For the reaction of an allylsilane, the use of 5 equivalents of
Scheme 5. Substrate scope with respect to the substituted vinylaziridine.
the alkene was necessary for full consumption of the vinyl-
aziridine, and pyrrolidine 2u was obtained with modest cis
selectivity.[17] When an excess of 1-hexene was used, the
corresponding pyrrolidine 2v was generated in low yield.
Whereas the 1,2-disubstituted alkene norbornene provided
pyrrolidine 2w, cyclohexene was absolutely unreactive. When
electron-rich N-Boc-protected tetrahydropyridine was used
as a reactive substrate, 2x was obtained with exceptionally
high cis selectivity. The reaction of 1-methylidene-1,2,3,4-
tetrahydronaphthalene yielded spirocyclic 2y, which can be
used for the synthesis of a b-secretase inhibitor (see the
Supporting Information),[18] in near-quantitative yield.
Although the product was not formed when other N-protect-
ing groups, such as tert-butoxycarbonyl and benzyl, were used
on the vinylaziridine, the nosyl group was found to be
applicable to this catalysis, thus enabling the synthesis of 2z in
good yield.
Reaction conditions: N-tosyl vinylaziridine 1 (0.10 mmol), alkene
(0.12 mmol), 6c (0.06 mmol), 2–12 h. The combined yield of the diaste-
reomeric products is given in each case. Diastereomeric ratios (trans/cis)
1
were determined by H NMR analysis of the crude material. The structure
of the major diastereomer is shown. [a] Disulfide: 10 mol%. [b] Alkene:
10 equivalents. [c] D.r.: 2,3-cis,3,4-cis/2,3-trans,3,4-trans/2,3-cis,3,4-trans/
2,3-trans,3,4-cis. Cy=cyclohexyl, nd=not detected.
these cases. Substitution of the aziridine ring with an alkyl
group had a substantial effect on the reactivity. A reaction
with 2-methyl-2-vinylaziridine gave the corresponding pyrro-
lidine 7d in modest yield. Reactions of 2-alkyl 3-vinylazir-
idines were found to be slow and required an excess of tert-
butyl vinyl ether to provide sufficient amounts of the products
(7e–h). The diastereoselectivity of these reactions varied
depending on the bulk of the alkyl group, and among the four
possible diastereomers, the 2,3-cis/3,4-cis-pyrrolidine and 2,3-
trans/3,4-trans-pyrrolidine were obtained as major isomers.
These 2-alkyl 3-vinylaziridines were used as a mixture of
diastereomers, since the bulky thiyl radical effectively facil-
itates the epimerization of the vinylaziridine to give the
thermodynamically more stable cis isomer as shown in
Equation (1).
We further extended our method to the use of substituted
vinylaziridines (Scheme 5). Substitution of the internal
carbon atom of the vinyl moiety with an alkyl or aryl group
did not affect the reactivity of the vinylaziridine; thus, 7a–c
were obtained in good yield. Contrary to expectation, the
more congested cis isomer became the dominant product in
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Scheme 6. Thiyl-radical-catalyzed [3+2] cyclization of N-tosyl vinylazir-
idine with C60 fullerene.
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reaction of N-tosyl vinylaziridines with a variety of alkenes
under the catalysis of sterically hindered thiyl radicals.[22]
Mechanistic analysis allowed us to identify steric bulk as the
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[14] We also observed the same tendency when the reactions were
carried out with the chiral thiyl-radical catalyst developed in our
previous study (Ref. [7]), although the enantioselectivity was
promising. Product 2a was obtained in 18% yield with d.r. 71:29
and 44/23% ee, and 2b was obtained in 6% yield with d.r. 71:29
and 43/35% ee.
is a common termination pathway of thiyl-radical-mediated
reactions,[1] thus potentially opening up new possibilities for
thiyl-radical catalysis. Moreover, the fundamental results
presented herein should enable the development of new
stereoselective applications of thiyl-radical catalysts.
Acknowledgements
This research was partially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan. T.H. acknowledges
a Grant-in-Aid for Scientific Research (B).
Keywords: pyrrolidines · radical reactions · sulfur · thiyl radicals ·
vinylaziridines
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[16] The configuration of representative products was determined by
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Received: March 18, 2016
Published online: && &&, &&&&
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Communications
Radical Reactions
T. Hashimoto, K. Takino, K. Hato,
K. Maruoka*
&&&& — &&&&
A Bulky Thiyl-Radical Catalyst for the
[3+2] Cyclization of N-Tosyl
Vinylaziridines and Alkenes
Bulk it up: A thiyl-radical-catalyzed cycli-
zation reaction of N-tosyl vinylaziridines
and alkenes was developed as a new
synthetic method for the generation of
substituted pyrrolidines (see scheme).
The key to making this process accessible
to a broad range of substrates is the use
of a sterically demanding thiyl radical to
prevent the undesired degradation of the
catalyst.
6
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!