Aminoxylation of Thioalkynes through Radical-Polar Crossover

Article abstract of DOI:10.1055/s-0039-1689925

A one-pot procedure for the aminoxylation of thioalkynes for the direct formation of α-functionalized thioesters under mild reaction conditions is reported. A ketenethionium ion is the key intermediate, which is generated in situ by Bronsted acid mediated protonation and undergoes a radical-polar crossover.

Full text of DOI:10.1055/s-0039-1689925

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–C
letter
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G. Di Mauro et al.
Letter
Synlett
Aminoxylation of Thioalkynes through Radical-Polar Crossover
Giovanni Di Mauro
O
N
Martina Drescher
O
Sara Tkaczyk
9 examples
up to 65% yield
radical-polar crossover
S
Nuno Maulide*
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0-
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3-3
6
4
3-0
7
1
8
O
TfOH
S
N
radical-polar crossover
aminoxylation reaction
Institute of Organic Chemistry, University of Vienna,
Währinger Strasse 38, 1090 Vienna, Austria
nuno.maulide@univie.ac.at
Published as part of the ISySyCat2019 Special Issue
Received: 06.03.2019
Accepted after revision: 10.05.2019
Published online: 03.06.2019
Reactivity pathways that allow the direct formation of
-functionalized thioesters from thioalkynes are of even
greater interest. In this context, our group and others have
engaged thioalkynes in acid-catalyzed arylative rearrange-
ments employing arylsulfoxides,7,8 while Zhao and Sun
have exploited scandium catalysis to access substituted ,-
unsaturated thioesters.9 Following our recent report on the
acid-promoted reaction of TEMPO with activated ynamides
(Scheme 1, b),10 we were eager to extend those investiga-
tions to thioalkynes. Herein, we report the development of
an aminoxylation of thioalkynes as well as several intrigu-
ing mechanistic features of the process.
DOI: 10.1055/s-0039-1689925; Art ID: st-2019-b0138-l
Abstract A one-pot procedure for the aminoxylation of thioalkynes for
the direct formation of -functionalized thioesters under mild reaction
conditions is reported. A ketenethionium ion is the key intermediate,
which is generated in situ by Brønsted acid mediated protonation and
undergoes a radical-polar crossover.
Key words thioalkynes, aminoxylation, radical-polar crossover, thio-
ester
Alkynes are privileged, versatile functional groups in or-
ganic synthesis.1,2 Juxtaposing an alkyne and a sulfur atom
leads to thioalkynes or alkynylsulfides, an interesting class
of electron-rich acetylenes.3 Thioalkynes serve as interest-
ing precursors to thioesters,4–6 offering an alternative to the
classical synthetic approach of combining a thiol and an
acyl chloride. Indeed, the direct acidic hydrolysis of alkynyl-
sulfides delivers thioesters in a mild manner (Scheme 1, a).
We started our investigations using nonyne-derived
alkynylsulfide 1a and employing conditions akin to those
previously employed for ynamides. In the event (Table 1),
dichloromethane proved to be the best solvent. Thus, pre-
activation of the thioalkyne using TfOH for 15 minutes at
0 °C followed by addition of 3 equivalents of TEMPO, warm-
Table 1 Optimization of the Reaction Conditions
a)
O
Brønsted acids, SiO2, CH2Cl2
O
TfOH (1.1 equiv), T (°C), 15 min
then TEMPO (equiv), T (°C), time (h)
R2
C7H15
N
S
C7H15
S
N
S
O
Me
S
1a
2a
O
b)
O
O
TfOH (1.1 equiv), 0 °C, 15 min
then TEMPO (3.0 equiv), 25 °C, 16 h
N
O
O
Solvent
[M]
Temp
(°C)
TEMPO
(equiv)
Time
(h)
Isolated yield
(%)
O
N
O
CH2Cl2[0.1]
CH2Cl2[0.1]
CH2Cl2[0.1]
CH2Cl2[0.1]
0 to 25
0 to 25
0 to 25
2.2
3
12
4
39
58
70
36
48
0
This Work:
S
TfOH (1.1 equiv), 0 °C, 15 min
then TEMPO (3.0 equiv), 25 °C, 16 h
S
O
N
3
16
16
16
16
–78 to 25
0 to 25
3
Scheme 1 Generic pathways for conversion of (a) thioalkynes to thio-
esters, (b) aminoxylation of ynamides, and (c) aminoxylation of thioesters
C2H4Cl2[0.1]
CH3CN [0.1]
3
0 to 25
3
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–C
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
G. Di Mauro et al.
Letter
Synlett
ing up to room temperature, afforded the product 2a in re-
producible 70% yields. Lower temperatures during the acti-
vation event proved not to be beneficial.
connected to a mechanistic scenario whereby 2 equivalents
of the persistent aminoxyl radical are incorporated in the
final product.
Having identified suitable conditions for the transfor-
mation, the scope of the reaction was investigated (Scheme
2). Alkyl substitution on the thioalkyne partner was tolerat-
ed (2a–c),11,12 affording the aminoxylation products in
moderate yields due to the formation of relatively complex
mixtures of unidentifiable byproducts, from which chro-
matographic isolation of the desired adducts was trouble-
some. Cyclopropyl substitution was also accommodated
without any ring-opening products being detected (2d).
Protected nitrogen moieties (cf. phthalimide 2e) did not in-
terfere with the transformation. An ester (cf. 2f) and a pri-
mary halide (cf. 2g) could also be tolerated.
N
O
R2
H
S
N
H
R2
radical
recombination
O
radical-polar
crossover
R1
O
N
S
•
R1
O
N
R2
R2
H
S
N
O
S
R1
O
N
R1
O
N
B
A
H2O
O
TEMPOH
TfOH (1.1 equiv), 0 °C, 15 min
then TEMPO (3.0 equiv), 25 °C, 16 h
S
2
O
N
S
Scheme 3 Proposed mechanism
1
2
The presence of an aryl moiety directly attached to the
thioalkyne (R1 = Ar), such as in 2h, is likely to stabilize inter-
mediate A. A similar stabilizing effect can be anticipated for
S-aryl thioalkynes (R2 = Ar), such as in 2i. The reason for the
experimentally observed lower yields and more complex
mixtures in the case of those substrates can thus be as-
cribed to either a higher barrier to radical recombination or
a propensity of the more stabilized A to undergo deleteri-
ous side reactions (see Supporting Information for unsuc-
cessful attempts on related substrates). Product 2b was
amenable to reductive N–O cleavage affording product 3a in
81% yield (Scheme 4).
O
O
O
S
S
S
O
O
O
N
N
N
2a
70%
2b
30%
2c
53%
O
O
O
O
O
N
O
O
N
S
S
O
S
N
O
N
O
2d
44%
2e
57%
2f
37%
O
Zn (15.0 equiv), AcOH, H2O,
CH2Cl2 (0.1 M), 25 °C, 48 h
C6H13
N
O
S
Cl
C6H13
OH
O
S
81%
O
O
O
2b
3a
S
S
S
O
O
O
N
Scheme 4 Reductive N–O bond cleavage
N
N
2g
65%
2h
21%
2i
6%
In summary, we have developed an aminoxylation of
thioalkynes that proceeds by a radical-polar crossover
mechanism. The process involves addition of a radical spe-
cies to a ketenethionium intermediate that ultimately
evolves to an -aminoxylated thioester.
Scheme 2 Substrate scope for the aminoxylation of thioalkynes
Aromatic residues either attached to the thioalkyne
(2h) or directly bound to sulfur (–SPh, cf. 2i) led to signifi-
cantly lower yields. Mechanistically and in analogy to our
prior work,10 we surmise that after protonation of the thio-
alkyne a radical-mediated C–O bond formation takes place.
This leads to a sulfur-centered radical cation A for which
two mesomeric forms can be depicted (Scheme 3). The re-
quirement for an excess of TEMPO is, as before, most likely
Funding Information
Generous funding by the European Research Council (Grant No. CoG
VINCAT 682002) and the Austrian Science Fund (FWF, Grant No.
P32206) is acknowledged.
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© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–C

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Acknowledgment
(8) Kaldre, D.; Maryasin, B.; Kaiser, D.; Gajsek, O.; González, L.;
Maulide, N. Angew. Chem. Int. Ed. 2017, 56, 2212.
We are grateful to the University of Vienna for continued support of
our research programs. Expert analytical support by E. Macoratti
(University of Vienna) and NMR analysis by Dr. H. Kählig (University
of Vienna) are acknowledged.
(9) Liu, B.; Wang, Y.; Chen, Y.; Wu, Q.; Zhao, J.; Sun, J. Org. Lett.
2018, 20, 3465.
(10) Pinto, A.; Kaiser, D.; Maryasin, B.; Di Mauro, G.; Gonzàles, L.;
Maulide, N. Chem. Eur. J. 2018, 24, 2515.
(11) General Procedure for the Synthesis of 2
To a solution of the thioalkyne (1.00 equiv) in CH2Cl2 (0.1 M) in
a flame-dried Schlenk tube, trifluoromethanesulfonic acid (1.10
equiv) was added, and the mixture was stirred for 15 min at
0°C. TEMPO (3.00 equiv) was added in one portion, and the
resulting solution was allowed to warm up to 25 °C and stirred
over 16 h. The reaction was quenched by addition of a saturated
aqueous solution of NaHCO3. The product was extracted with
CH2Cl2, and the resulting organic phase was dried over Na2SO4,
filtered, and the solvent was evaporated under reduced pres-
sure. The product was purified by flash chromatography on
silica gel using heptane methyl-tert-butyl ether as eluent.
(12) Analytical Data for Compound 2c
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1689925.
S
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References and Notes
(1) Trost, B. M.; Weiss, A. H. Angew. Chem. Int. Ed. 2007, 46, 7664.
(2) Trost, B. M.; Tracy, J. S. Isr. J. Chem. 2018, 58, 18.
(3) Frei, R.; Wodrich, M. D.; Hari, D. P.; Borin, P.-A.; Chauvier, C.;
Waser, J. J. Am. Chem. Soc. 2014, 136, 16563.
(4) Braga, A. L.; Martins, T. L. C.; Silveira, C. C.; Rodrigues, O. E. D.
Tetrahedron 2001, 57, 3297.
(5) Hoshi, M.; Masuda, Y.; Arase, A. Bull. Chem. Soc. Jpn. 1990, 63,
447.
(6) Racine, S.; Hegedüs, B.; Scopelliti, R.; Waser, J. Chem. Eur. J.
2016, 22, 11997.
1H NMR (400 MHz, CDCl3):  = 3.75 (d, J = 8.8 Hz, 1 H), 2.28 (s, 3
H), 1.65–1.40 (br, 6 H), 1.30 (br, 3 H), 1.18 (br, 6 H), 1.12–1.06
(m, 1 H), 1.03 (br, 3 H) 0.75–0.45 (m, 4 H). 13C NMR (151 MHz,
CDCl3):  = 201.4, 94.5, 40.3 (2 C), 34.4, 33.5, 20.4, 20.1, 17.1,
15.1, 10.9, 7.5, 2.05 (quaternary carbons in the TEMPO moiety
not visible in 13C NMR). HRMS (ESI+): m/z calcd for
(C15H28N2OS+) [M + H]+: 286.1835; found: 286.1830. IR (neat):
(7) Hu, L.; Gui, Q.; Chen, X.; Tan, Z.; Zhu, G. J. Org. Chem. 2016, 81,
4861.

max = 3005, 2972, 2929, 2359, 1684, 1465, 1376, 900 cm–1
.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–C