Redox-Neutral Synthesis of Selenoesters by Oxyarylation of Selenoalkynes under Mild Conditions

Article abstract of DOI:10.1021/acs.orglett.8b02544

An approach for the mild synthesis of selenoesters starting from selenoalkynes through an acid-catalyzed, redox-neutral oxyarylation reaction is reported. Br?nsted acid activation of a selenoalkyne leads to a selenium-stabilized vinyl cation, which is cap

Full text of DOI:10.1021/acs.orglett.8b02544

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Redox-Neutral Synthesis of Selenoesters by Oxyarylation of
Selenoalkynes under Mild Conditions
Lucas L. Baldassari,†,§ Anderson C. Mantovani,†,§ Samuel Senoner,‡,§ Boris Maryasin,‡
,†
Nuno Maulide,*,‡ and Diogo S. Ludtke*
̈
†Instituto de Química, Universidade Federal do Rio Grande do Sul, UFRGS, Av Bento Gonca
̧
lves 9500, 91501-970 Porto Alegre,
RS, Brazil
‡
̈
Institute of Organic Chemistry, University of Vienna, Wahringer Straße 38, 1090 Vienna, Austria
S
* Supporting Information
ABSTRACT: An approach for the mild synthesis of selenoesters starting from selenoalkynes through an acid-catalyzed, redox-
neutral oxyarylation reaction is reported. Brønsted acid activation of a selenoalkyne leads to a selenium-stabilized vinyl cation,
which is captured by an aryl sulfoxide and undergoes sigmatropic rearrangement to deliver the final α-arylated selenoester
product. Computational studies have been carried out to elucidate the nature of the Se-stabilized carbocation.
a
Table 1. Optimization of the Reaction Conditions
elenoesters are versatile functional groups in synthetic
Sorganic chemistry. They have been used as mild acyl-
transfer agents,1 as acyl-radical precursors,2 for heterocycle
Scheme 1. Key Precedents and This Work
b
entry
TfOH (equiv)
solvent
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
1.0
0.5
0.1
0.1
0.1
0.1
0.1
0.1
0.1
CH2Cl2
CH2Cl2
CH2Cl2
DCE
1
1
1
1
1
1
1
1
1
60
80
86
40
32
35
18
17
75
PhCl
toluene
hexane
THF
a
The reaction was performed in the presence of 1a (0.25 mmol) and
b
2 (0.50 mmol). Yield determined by NMR spectroscopy using
mesitylene as the internal standard.
synthesis,3 in asymmetric aldol reactions,4 and as key
intermediates for the incorporation of the amino acid
selenocysteine (and other selenoamino acids) in peptides
through the native chemical ligation method.5 In addition,
selenoesters have found applications in pharmaceutical6 and
material sciences.7 The vast majority of the methods available
for the synthesis of selenoesters typically employ acyl chlorides
and a nucleophilic selenium source (Scheme 1A).8 Other
Received: August 8, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02544
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Scope of the Selenoalkyne
approaches include oxidative coupling of aldehydes and
diphenyl diselenide,9 addition of organocopper reagents to
carbonyl selenide (SeCO),10 a reaction of carboxylic acids with
aryl selenocyanates11 and Pd-catalyzed coupling of PhSeSnBu3
with acyl chlorides.12 The hydrolysis of alkynyl selenides has
also been reported.13 Despite the wealth of available methods,
selenoesters are not easy to synthesize, and the reported routes
can be cumbersome, with substrate scope frequently limited to
simple (usually aromatic) substrates.
Herein, we present an original approach starting from
selenoalkynes through an acid-catalyzed, redox-neutral oxy-
arylation reaction. The concept can be traced back to our
previous studies on acid-mediated activations of ynamides in
which a nitrogen-stabilized vinyl cation intermediate was
generated (Scheme 1B).14,15 We reasoned that this concept
could be extended to selenoalkynes, and thus, a selenium-
stabilized vinyl cation would result from the reaction with
TfOH.16
This intermediate might then be intercepted by an aryl
sulfoxide, which in turn would be poised to undergo a Claisen-
type [3,3]-sigmatropic rearrangement, ultimately delivering an
α-arylated selenoester product (Scheme 1C).
At the outset, we selected selenoalkyne 1a and diphenyl
sulfoxide as model substrates for the optimization of the
oxyarylation conditions. Selected results are summarized in
Table 1.17 In initial experiments employing a full equivalent
(1.0 equiv) of TfOH, the product 3a was obtained in 60% yield
(entry 1). Aiming to render the reaction catalytic, we lowered
the amount of TfOH to 0.5 and 0.1 equiv, and gratifyingly, the
arylated selenoester was obtained in 86% yield using only 10
mol % of triflic acid (entry 3). A solvent screening was also
carried out, revealing that dichloromethane outperforms all
other solvents investigated (entries 3−8). It should be noted
that an efficient reaction was observed without solvent, albeit at
slightly decreased yield (entry 9). On the basis of these studies,
the two best conditions shown in entries 3 (conditions A) and
9 (conditions B) have been selected for further screening of
the substrate scope using a broader range of selenoalkynes
(Scheme 2).
A number of selenoalkynes with different substitution
patterns have been studied. Variations at the R2 group attached
to the selenium atom have shown that alkyl (3a−d) and
benzylic (3e) groups were well tolerated under the reaction
conditions. Noteworthy is the tolerance to the presence of a
primary alkyl chloride, with the corresponding product 3d
being formed in 86% isolated yield.
Arylselenoalkynes were also examined, and the correspond-
ing selenoesters 3f−k were obtained in good yields. The
presence of chlorine, methoxy, phenyl, and trifluoromethyl
groups was well tolerated as well as the presence of an ortho
substituent. Variations at the R1 position have also been
performed, and selenoalkynes bearing longer linear alkyl chains
resulted in the desired selenoester product in good yields.
Additionally, a cyclohexenyl substituent at the selenoalkyne
also resulted in the corresponding product 3u, albeit in low
B
DOI: 10.1021/acs.orglett.8b02544
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Organic Letters
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Scheme 3. Scope of the Sulfoxide
Figure 2. (Left) Relative Gibbs free energies of selenoalkynes and
sulfur−alkynes (the alkynes are taken as references) and correspond-
ing seleno and sulfur vinyl cations calculated at the B3LYP-D3-SMD/
def2-TZVP level of theory. (Right) Stabilizing donor−acceptor
interactions.
yield. Finally, using an unsubstituted selenoalkyne delivered
the selenoester 3v in 79% yield.
We next turned our attention to the scope of the aryl
sulfoxide reaction partner (Scheme 3). Both electron-donating
Figure 1. Computed reaction profiles (B3LYP-D3-SMD/6-31+G(d,p), ΔG298,DCM) for the conversion of sulfur−alkyne (red) vs selenoalkynes
(green) into the final product F. The energy of the reactant complex A is taken as a reference (0.0 kcal mol−1).
C
DOI: 10.1021/acs.orglett.8b02544
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and electron-withdrawing groups were successfully used (4a−
f). Importantly, alkylaryl sulfoxides are also competent
nucleophiles for oxyarylation, and smooth aryl transfer was
observed (4g−j). Using symmetric 4-tolyl(phenyl) sulfoxide
led to selective transfer of the phenyl group leading to product
4j. In our hands, the oxyarylation products appear to
decompose upon prolonged exposure to light, presumably
due to facile cleavage of the labile carbonyl−Se bond. While
such a cleavage is likely to be of homolytic nature when
induced by light, it should be noted that selenoester 4d
underwent hydrolysis during silica gel chromatographic
purification. That compound was thus ultimately isolated as
the corresponding carboxylic acid. In contrast to selenium-
stabilized alkyl carbocations, long known in the literature,18
vinyl carbocations have been largely overlooked and rarely
explored or proposed as intermediates in organic synthesis.19
Therefore, in order to further elucidate the mechanism of the
reaction, a computational study was carried out (Figure 1).
In this study, thio- and selenoalkyne substrates were
analyzed comparatively. Figure 1 compares the computed
reaction profiles for the conversion of thio- (red) and
selenoalkynes (green) into the final product. The two
considered substrates show similar energetic behavior. The
overall reaction is exergonic for both systems, and the barriers
are relatively low, in agreement with the mild reaction
conditions.
The most significant distinction between the computed
sulfur and seleno pathways is the stability of intermediates B
ternary complexes of vinyl cations, sulfoxides, and triflate
anions. While this energy difference might be the result of
intermolecular interactions within the complexes B, it appears
reasonable to assume the nature of the vinyl cations
selenium- vs sulfur-stabilized vinyl cationscan cause this
effect. To validate this assumption, we have reoptimized the
structures of the alkyne (part of the complex A) and vinyl
cation (part of the complex B) for both cases, separately from
sulfoxide, TfOH, and TfO−. For these simplified systems, we
have improved the computational approach applying the larger
basis set def2-TZVP. Figure 2 (left) shows that for both seleno
and thio systems the alkynes are, unsurprisingly, more
stabilized than the vinyl cations (in agreement with the results
shown in Figure 1) and the energy gap is ∼1 kcal mol−1
smaller in the case of selenium. The latter is also in accordance
with the computed reaction profiles (Figure 1). Thus, the
electronic structures of the alkynes and the vinyl cations, rather
than the intermolecular interactions within reaction inter-
mediates, predetermine the computed energy gap.
donor−acceptor interaction is stronger for the selenium-
substituted vinyl cation than for its sulfur counterpart and vice
versa for the alkyne case; i.e., the thioalkyne is more strongly
stabilized than its selenium counterpart. Put in intuitive terms,
the larger polarizability of selenium20 appears to play the more
important role in vinyl cation stabilization (compared with
“size”-dependent orbital overlap efficiency, which could be
expected to be larger for sulfur and is predominant in
stabilization of the allene). This computationally documented
superior ability of selenium to stabilize the vinyl cation
intermediate should be of considerable significance in the
development of further chemistry of selenoalkynes.
In summary, we have reported herein the redox-neutral
oxyarylation of selenoalkynes as a mild and efficient approach
for the synthesis of selenoesters. The reaction involved the
activation of the triple bond to generate a selenium-stabilized
vinyl cation which was trapped with an aryl sulfoxide and
subsequently underwent a Claisen-type rearrangement to
afford the α-arylated sulfoxide product. The reported method
is a mild and complementary alternative to the previously
reported methods. Computational studies using DFT and
NBO analysis reveal that selenium is superior to sulfur in
stabilizing the vinyl cation intermediate, an observation likely
to have fundamental and practical implications for future work.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02544.
Experimental procedures, analytical data, copies of NMR
spectra, and computational details ((PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: nuno.maulide@univie.ac.at.
*E-mail: dsludtke@iq.ufrgs.br.
ORCID
Nuno Maulide: 0000-0003-3643-0718
Diogo S. Ludtke: 0000-0002-9135-4298
̈
Author Contributions
§L.L.B., A.C.M., and S.S. contributed equally.
Notes
The authors declare no competing financial interest.
To elucidate the factors responsible for stabilization, we have
performed a Natural Bond Orbital (NBO) analysis of the
alkynes and the vinyl cations for both cases. Figure 2 (right)
depicts the most important donor−acceptor interactions for
these systems. The interacting orbitals and the second-order
perturbation energies E(2) of these interactions are also
shown.
The vinyl cations are stabilized via an interaction between
the lone pair on sulfur/selenium atom and the σ*-
(antibonding) C1−C2 orbital. Analogously, there are inter-
actions between the lone pairs and the π*(antibonding) C1−
C2 orbitals for the corresponding alkynes. The fact that the
stabilization interactions are stronger for the alkynes than for
the vinyl cations is in agreement with the fact that vinyl cation
formation is an endergonic process (Figures 1 and 2).
However, as can be seen from Figure 2, the stabilizing
ACKNOWLEDGMENTS
We thank the Brazilian Agencies CNPq, CAPES, and INCT-
■
́
Catalise for financial support. Calculations were partially
performed at the Vienna Scientific Cluster (VSC). We thank
́
Prof. Leticia Gonzalez (University of Vienna) for fruitful
discussions and computational resources. Support of this
research by the European Research Council (CoG 682002
VINCAT) and the University of Vienna is gratefully
acknowledged.
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