Unconventional Reactivity of Ethynylbenziodoxolone Reagents and Thiols: Scope and Mechanism

Article abstract of DOI:10.1002/chem.201904520

1,2-Dithio-1-alkenes are biologically active compounds widely implemented throughout organic synthesis, functional materials, coordination chemistry, and pharmaceuticals. Traditional methods for accessing 1,2-dithio-1-alkenes often demand transition metal

Full text of DOI:10.1002/chem.201904520

A Journal of
Accepted Article
Title: Unconventional Reactivity of Ethynylbenziodoxolone (EBX)
Reagents and Thiols: Scope and Mechanism
Authors: Bin Liu, Juan Alegre-Requena, Robert Paton, and Garret
Miyake
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RESEARCH ARTICLE
Unconventional Reactivity of Ethynylbenziodoxolone (EBX)
Reagents and Thiols: Scope and Mechanism
Bin Liu,† Juan V. Alegre-Requena,† Robert S. Paton,*,†,‡ Garret M. Miyake*,†
Abstract: 1,2-Dithio-1-alkenes are biologically active molecules
widely implemented throughout organic synthesis, functional
materials, coordination chemistry, and pharmaceuticals. Traditional
methods for accessing 1,2-dithio-1-alkenes often demand transition
metal catalysts, specialized or air-sensitive ligands, high
temperatures, and disulfides (R2S2). Here, a general and efficient
strategy utilizing ethynylbenziodoxolone (EBX) reagents and thiols is
presented which results in the formation of 1,2-dithio-1-alkenes with
excellent regioselectivity and stereoselectivity through unprecedented
reactivity between the EBX and the thiol. This operationally simple
procedure utilizes mild conditions, resulting in a broad substrate
scope and high functional group tolerance. The observed and
unexpected reactivity has been rationalized through both
experimental results and density functional theory (DFT) calculations.
Introduction
Multisubstituted olefins are valuable building blocks and
precursors in organic chemistry.[1] 1,2-Dithio-1-alkenes are an ex-
ample of these compounds that have found widespread
Figure 1. (a) Reaction of EBX reagents and phenols under visible light
irradiation. (b) Initial hypothesis: Reactions of EBX reagents and thiols to form
(Z)-2-iodovinyl phenyl thioethers. (c) This work: Reaction of EBX reagents and
thiols to form (Z)-1,2-dithio-1-alkenes. (d) Examples of bisthiolated alkene
application in organic synthesis,[2] functional materials,[3]
coordination chemistry,[4] and in pharmaceuticals (Figure 1d).[5]
Despite their synthetic utility, approaches for the synthesis of 1,2-
scaffold containing compounds.
dithio-1-alkenes leave room for improvement. Palladium,[6]
rhodium,[7] and nickel[8a] catalysts have been employed
extensively to promote the additions of disulfides (R2S2) to
alkynylbenziodoxoles with N-aryl imines and carboxylic acids[14]
terminal alkynes, forming (Z)-1,2-dithio-1-alkenes. Functional
and copper-catalyzed oxyalkynylation of diazo compounds.[15]
group tolerance is limited in these systems as these systems
Although several effective methods have been reported for the
require relatively sensitive catalysts, disulfides (R2S2), or harsh
transformation of EBX reagents, the vast majority of these focus
conditions. As such, the development of a mild, general, and
on the use of the EBX as an alkynylation agent. In contrast, the
versatile strategy tolerant to a range of functional groups is
addition of two equivalents of a (pro)-nucleophile to the
electrophilic C−C triple bond of EBX is widely underdeveloped.
Herein, we describe the discovery and development of this mode
therefore highly desirable.
Ethynylbenziodoxol(on)es (EBXs)[9] have demonstrated their
utility as electrophilic alkynylation reagents that readily engage a
of reactivity between EBX reagents and thiols where two
range of carbon,[10] sulfur,[11] nitrogen,[12] and phosphorus[13]
equivalents of thiol add to the C−C triple bond to produce (Z)-1,2-
bisthiolated alkene derivatives (Figure 1c). Experimental and
nucleophiles. Other reactions involving EBX reagents have also been
pursued, including the Pd(II)-catalyzed transformation of
computational
mechanistic
studies
indicate
that
cis
regioselectivity observed in the final products is through cis-
selective nucleophilic RSH addition followed by a cis-specific
radical RSH addition. This reaction constitutes a powerful
alternative to traditional processes for producing multisubstituted
olefins and can enable the rapid construction of molecular
complexity.
[*]
†Dr. Bin Liu, Dr. Juan V. Alegre-Requena, Prof, Robert S. Paton
and Prof, Garret M. Miyake
Department of Chemistry, Colorado State University
Fort Collins, Colorado, 80523 (USA).
E-mail: garret.miyake@colostate.edu
robert.paton@colostate.edu
Our interest in visible light-driven and transition metal free
chemistry [16] recently led to the development of a visible-light-
promoted reaction of phenols and EBX reagents in the presence
of Cs2CO3 to form (Z)-2-iodovinyl phenyl ethers (Figure 1a). This
transformation occurs via the formation of an electron donor-
acceptor (EDA) complex in which an electron is transferred from
Homepage: https://wp.natsci.colostate.edu/miyakelab/,
http://patonlab.com/
‡Chemistry Research Laboratory, University of OxfordMansfield
Road, Oxford, OX1 3TA (UK).
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201904520
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the phenoxide anion to the vinylbenziodoxolone.[17] We also
previously disclosed that thiophenoxide can act as an electron
donor under visible light irradiation, forming an EDA complex with
aryl halides en route to the construction of C−S bonds.[18] Based
on these previous electron donor-acceptor protocols, we
questioned whether it would be possible to access (Z)-2-iodovinyl
phenyl thioethers from EBX reagents by using thiophenols as the
electron donor (Figure 1b).
(3o, 3p). However, presence of a chlorine atom on the alkyl-EBX
led to substitution by an aromatic thiol (3m). In addition, t-butyl
and tetradecyl-EBX reacted with methyl thiosalicylate to form the
corresponding product in 42% and 35% yield, respectively (3n,
3q). Importantly, all EBX reagents give the desired bisthiolated
alkenes with Z-selectivity. Markedly, the thio-alkyne product could
be isolated with triisopropylsilyl-EBXs under the standard reaction
conditions (see SI pS14). The configuration of 3c-d, 3m-p was
determined by using nuclear Overhauser effect spectroscopy
(NOESY) analysis (see SI, pS4).
Results and Discussion
Table 1. Summary of Reaction discovery and optimization.
A principal concern in the development of the targeted
process was the competitive reaction between thiols and EBX
reagents to form thio-alkynes.[11] To investigate the feasibility of
our hypothesis, we examined similar conditions to our previously
reported reaction between EBX and phenols (1.5 equiv 2b, 1.5
equiv Cs2CO3 in 0.01 M CH3CN under blue light irradiation at
room temperature) (Table 1, entry 1).[16] Contrary to our
expectation, the unexpected dithioalkene product 4h was
1
obtained on the basis of crude H NMR analysis. Compared to
Entry
1
T (h)
10
Eq (2b)
1.5
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
1.0
2.0
3.0
4.0
4.0
4.0
4.0
4.0
Solvent
CH3CN
CH3CN
CH3CN
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMF
Base
Yield (%)
40[a]
78[a]
75[b]
96
thio-alkynylation products obtained in previous EBX reactions,[11]
this product is indicative of a new and complementary mode of
reactivity. Subsequently, we observed substantial improvement in
the yield of 4h by improving the loading of 2b to 4.0 equiv. (entry
2). However, control experiments revealed that the desired
product was also detected in good yield (entry 3) in the absence
of blue light irradiation or in complete darkness (entries 3 and 8).
Upon further investigation, we identified N,N-dimethylacetamide
or N,N-dimethylformamide as optimal solvents (Table 1, entries 7,
9, 10, 14-17), and employed 4.0 equivalents of 2b with Cs2CO3
as base to achieve good yields (entries 7, 11-13). In screening
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
TBD
2
10
3
10
4
10
5
10
65[c]
86
6
10
7
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
Cs2CO3
Cs2CO3
Na2CO3
K2CO3
95(93[d]
81[b]
71
)
other
bases,
we
observed
reduced
yields
with
8
triazabicyclodecene, Na2CO3, and K2CO3 (entry 6, 9-10, 18).
Notably, 85% yield of product was achieved in the presence of
water (Table S1, entry 14). We employed high purity bases,
including Cs2CO3 (99.995%) and K2CO3 (99.995%), and
observed similarly high yields, suggesting that trace impurities are
not responsible for this transformation (Table S1, entry 20-21).
9
10
11
12
13
14
15
16
17
18
82
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
TBD
30
70
77
Encouraged by these initial results, we investigated the
scope of reactivity with respect to the EBX reagent. As shown in
Scheme 1, mercaptobenzothiazoles reacted with a variety of
aromatic and functionalized alkyl-EBX reagents. Para-methyl
substituted Ph-EBX is tolerated, affording the desired product in
71% yield, while presence of a methyl substituent at the ortho
position of the aryl ring significantly reduced the yield (3c, 3d).
Substrates with either electron-withdrawing groups (cyano, ester,
aldehyde, bromo and trifluoromethyl) or electron-donating groups
(methyl and methoxy) underwent transformation efficiently to
afford the corresponding (Z)-1,2-bis(arylthio)alkene derivatives
(3b, 3e–3l) in good yields (69–92%). Furthermore, the functional
group tolerance of the alkyl-EBX reagents was highlighted by the
successful synthesis of (Z)-1,2-bis(arylthio)alkenes bearing
hydroxy and alkene groups in 63% and 83% yield, respectively
98
DMSO
CH3CN
THF
86
64
60
THF
40
Reaction conditions: Room temperature, N2. Yields are based on
2b, determined by 1H NMR using 1,3,5-trimethoxybenzene as
internal standard. [a] Under blue light; [b] protected from light with
[c]
[d]
foil;
under air;
Isolated yield; TBD, 1,5,7-
triazabicyclo[4.4.0]dec-5-ene; DMAc, N,N-dimethylacetamide;
DMF, N,N-dimethylformamide; DMSO, dimethyl sulfoxide; THF,
tetrahydrofuran.
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Scheme 1. Scope of Ethynylbenziodoxolones. a(5-Chloropent-1-ynyl)-1,2-benziodoxol-3(1H)-one.
We next evaluated the thiol scope and found that a number
of aliphatic and aromatic thiols were compatible under the
standard reaction conditions (Scheme 2). Additionally, primary
(4c, 4e, f), secondary (4b), and tertiary alkyl thiols (4a, 4d) were
suitable. Aromatic thiols were broadly applicable, regardless of
the steric and electronic properties of the aryl ring. As shown in
Scheme 2, aromatic building blocks bearing common functional
groups (methyl, methoxy, bromo, trifluoromethyl, and ester) are
well tolerated under the reaction conditions, and the
corresponding products were isolated in moderate to good yields
(4h-o). Transformations with benzenethiol and 2-naphthalenethiol
proceeded with 85% (4g) and 74% (4p) yield, respectively. To
further support the functional group tolerance of the reaction, we
turned our attention to the scope of heterocyclic thiols, which
provide access to ubiquitous motifs found in pharmaceuticals,
biologically active molecules, and agrochemicals. Alkenes
containing heterocyclic rings, such as benzo[d]thiazole, pyridine,
1H-benzo[d]imidazole, 1-methyl-1H-imidazole, benzo[d]oxazole,
4,5-dihydrothiazole, quinoline, pyrimidine, furan, and coumarin
could be converted effectively to the corresponding products
(4q−y) in moderate to good yields. In addition, motivated by their
unique electronic and biological properties,[20] we established a
synthetic route to benzo-1,4-dithiins through the use of (4z-ab)
benzene-1,2-dithiol. To demonstrate the potential synthetic value
of this transformation, 4.0 mmol of the Ph-EBX reagent was
subjected to the standard conditions to form the corresponding
products in good yield (4c, 4h, 4l). The configurations of 4c, 4v
and 4w were determined by NOESY (see SI, pS7).
Alkenylthioglycosides are important structural motifs that
exist in many biologically active compounds, as exemplified by
leaf-closure glycosidase inhibitors.[21] They can also be
transformed to alkylthioglycosides,[22] a reaction which can
increase the diversity of thioglycoside family. The transition metal
catalyzed alkenylation of thioglycosides has been reported
recently,[23] in which there is only one example of a bis-β-
thioglycoside alkene. Herein, we disclose a conceptually different
approach to bis-β-thioglycoside alkene derivatives based on EBX
reagents, highlighting reactivity complementary to that of
transition metal catalysts. In this process, stereoselectivity was
observed and the Z:E ratio is shown in Scheme 3. Overall, the
transformation tolerates both electron withdrawing and donating
groups (5b-d), making this an attractive method for preparing
alkenylthioglycosides. The configuration of 5b was determined by
NOESY (see SI, pS8). To our delight, good yield and excellent
stereoselective were obtained with vinylbenziodoxolones,
providing the alkenylthioglycoside 5e as a single E-isomer.
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Scheme 2. Thiol scope. aReaction conditions: 1 (4.0 mmol), 2 (16.0 mmol), Cs2CO3 (16.0 mmol), dimethylacetamide (20 mL), 20 hours, room temperature, N2.
Isolated yield reported. b0.4 mmol benzene-1,2-dithiol.
Scheme 3. Reactions of thioglycoside with Ph-EBX. a(E)-1-styryl-1,2-benziodoxol-3-(1H)-one was used.
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To understand the unconventional reactivity patterns
between ethynylbenziodoxolone (EBX) reagents and thiols de-
scribed above a combined experimental and computational
mechanistic study was undertaken. Calculations were performed
with dispersion-corrected density functional theory (DFT)[24] with
ωB97X-D/def2-QZVPP single point energies computed at
stationary points optimized at the ωB97X-D/6-311+G(d,p)[25-27]
level of theory (6-311G(d,p) for I atoms). The involvement of
anionic species (described below) necessitated the inclusion of
diffuse basis functions for non-hydrogenic atoms during all stages
of the investigation. Solvation by DMAc was described by the
SMD continuum solvation model in the optimizations and single-
point corrections.[28] In benchmark studies performed on
geometric and thermodynamic properties of hypervalent iodine
species, the ωB97X-D functional with valence triple- polarized
basis set ranked highly.[29] In our studies, the use of alternate
basis sets (e.g., def2-TZVPPD) to describe the I atom during
geometry optimization gave unchanged geometries (Figure S6a)
and had minimal impact upon computed energy profiles
computed at 1 M concentration and 298.15 K (Figure S6b).
Firstly, we analyzed the effect of the salt used in the reaction.
In the absence of Cs2CO3, the desired product could also be
1
detected in 30% yield by crude H NMR (Figure 2a). However,
the addition of different salts accelerates the reaction dramatically,
in accordance with the anion’s basicity (Cs2CO3 > Na2CO3 > CsF
> CsI > KPF6). The type of metal employed as the cation does not
affect the reaction yield to a great extent and most likely it only
modulates the basicity of the counteranion (i.e. Cs2CO3 and
Na2CO3 lead to 83% and 80% yield, respectively). Taking into
account the fact that thiophenols are much more acidic than
phenols in non-aqueous solvent (e.g., in DMSO thiophenol pKa
=10.3, vs. 18.0 for phenol),[30] the above data suggest that the
formation of a deprotonated thiol to form a thiolate is required for
an efficient reaction. [11b]
2.34
2.51
Figure 2. (a) Reaction yields obtained using different salts as additives. (b) Computed pathways for the addition of RS nucleophile to PhEBX (Gibbs energies in
kcal/mol, distances in Å).
Prompted
by
these
experimental
findings,
we
isomerization via C=C-I angle-bending is 15.9 kcal/mol, whereas
lower energy pathways exist toward different fates for this species
(Figure 2b). Loss of an iodophenylacetate anion is one such
pathway to form carbene 12, itself able to undergo a 1,2-shift to
form the thioalkyne consistent with previously reported
experimental and computational studies. The absence of such
product in our experimental studies suggests an alternative fate,
namely protonation of the β-cis-carbanion to form cis-
vinylbenziodoxolone thioether 7, is instead operative. Indeed,
using sub-stoichiometric quantities of base, Waser and coworkers
have previously reported products analogous to 7, presumably as
the result of protonation of carbanionic intermediates.[31]
Experimentally, we were able to observe the formation of 7 under
standard reaction conditions after 5 mins (Figure 3a). The
conversion of 7 to 1,2-dithio-1-alkene 8 was also successful, in
addition to the conversion of 9 to provide vinyl sulfide 10 (Figure
computationally evaluated reaction pathways for the addition of a
thiophenolate (pTolS) to PhEBX (Figure 2b). Additionally, we
considered the possibility of RS• radicals reacting with EBX. We
located transition structures (TSs) for the initial C-S bond
formation at both α- and β-positions of the alkyne, occurring either
cis- or trans-to the in-plane benziodoxolone group. The anionic
thiolate shows a kinetic preference for addition to the β-position,
with a high degree of cis-selectivity: this TS is 3.4 kcal/mol more
favorable than the trans-TS (Figure S2). The origins of this regio-
and stereo-selectivity, which is consistent with experimental
observations, are discussed in greater detail below. In contrast to
anionic pathways, thiyl radical additions favor the α-position of the
alkyne by 4.8 kcal/mol over β-addition (Figure S3). Our
calculations predict the resulting carbanionic intermediate to be
configurationally stable, since the barrier towards cis-trans
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3b). These observations are consistent with the intermediacy of
vinylbenziodoxolonesen route to the final 2-dithio-1-alkene
products. Additionally, the reactions of thiols with
vinylbenziodoxolones provide a convenient entry to vinyl sulfides
usually prepared by transition metal catalyzed cross-couplings.[19]
this second C-S bond forming event involves a thiyl radical, rather
than a thiolate. Sub-stoichiometric amounts of the free-radical
initiator 2,2’-Azobis(2-methylpropionitrile) (AIBN) were found to
promote product formation (Figure 4a). TEMPO trapping
experiments were also consistent with the formation of thiyl
radicals from the thiol pro-nucleophile, whereas no evidence for
radical formation was found for disulfide and sodium thiolate, both
of which fail to produce any 1,2-dithio-1-alkene product (Figure
4a and Control Experiments section in the ESI). The use of
sodium thiolate 2b’ gives rise to 7 without subsequent conversion
(Figure 4b). Collectively, these observations suggest that while
alkyne addition can be accomplished in the anionic manifold, the
second addition operates via a thiyl radical pathway. Accordingly,
the computed TS for C-S bond formation between 7 and a thiyl
radical was located for the α- and β-positions, with the α-TS being
more favorable by 11.6 kcal/mol (Figure S5). In a concerted, but
highly asynchronous fashion, the C-I bond is cleaved during this
step to produce a cis-configured 1,2-dithio-1-alkene. The low
barrier found for TS-II (10.9 kcal/mol, Figure 3b) suggests that
the rate-limiting step is not TS-II, but the RS• radical formation
from RSH that takes place before the second RSH addition. This
point is also supported by the catalytic effect of AIBN in conditions
where the rate-limiting step is the second radical addition (when
using Cs2CO3), which is probably caused by an acceleration of
RS• radical formation (see Control Experiments section in the ESI).
The involvement of RSH was also investigated computationally
but, in all the cases, the energy barriers of these processes were
considerably higher than the barrier of the radical pathway
(Figure S4).
Figure 3. (a) Vinylbenziodoxolone formation is observed in the early stages of
the reaction (1H NMR yield). (b) Conversion of vinylbenziodoxolones (isolated
yields).
Conversion of vinylbenziodoxolone 7 into the 1,2-dithio-1-
alkene product was probed experimentally and computationally.
Several experimental observations support the hypothesis that
TS-II α-cis
(ΔG‡ = 10.9 kcal/mol)
Figure 4. (a) AIBN promotes the reaction, while TEMPO trapping experiments implicate the formation of thiyl radicals. (b) Experimentally, TolSNa only leads to
vinylbenziodoxolone formation, while TolSH is required for 1,2-dithio-1-alkene formation. Yields were determined by 1H NMR.
The results suggest that the first RSH addition takes place
through a general base-promoted nucleophilic addition, since
radical additions lead completely to the α addition, which is
opposite to the experimentally observed results. This outcome is
not surprising since previous studies regarding EBX derivatives
α positions.[33] The nucleophilic preference toward the β addition
is consistent with the calculations of the condensed Fukui index,
f (r), which is a good quantitative predictor for the position of
+
attack (Table S2).[34] Higher values of f +(r) in C atoms are
associated with greater susceptibility toward nucleophilic attack.
It is worth mentioning that, contrary to previous studies where
other EBX derivatives were used,[11b,c] intermediate 7 is stable and
showed that nucleophilic attacks occur favorably at
β
positions[11b,17,32] while radical attacks take place preferentially at
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only leads to 4h and not to 11 or other isomers of 7 under the
experimental reaction conditions employed.
requires light to proceed while no light is needed when using RSH
nucleophiles. Also, reactions with RSH nucleophiles do not
change their outcomes when using light irradiation.
Experimentally, the addition of the first RSH molecule to form
7 is highly cis selective and this regioselectivity is pre-served
along the formation of final product 4h. A plausible explanation
behind the favored cis selectivity relies on the network of
noncovalent interactions formed in TS-I, the selectivity-
determining step of the first addition. More specifically, the main
difference between the β-cis and β-trans additions is the formation
of a stabilizing S--I halogen bond[35] in the transition state that
leads to the cis position (Figure 4), which might be the most
relevant factor favoring this regioselectivity (2.5 kcal/mol based on
NBO analysis). This halogen interaction mainly comprises the
orbital overlap of one of the S lone electron pairs and the σ* of the
C-I bond (nS→σCI*) and is potentially the driving force that led to
cis selectivity when using ROH in previous analogous additions
(Figure S8).[17]
It was suggested that the formation of product 14 is triggered
17]
by the HOMO / LUMO electron transfer depicted in Figure 6b.[
In fact, when this electron transfer process is emulated through
optimizing the geometries of anion radical versions of 13, the
products observed are analogous to 14 with ROH and RSH
(Figure S7). Interestingly, the orbital lobes involved in the electron
transfer are identical for RSH and ROH, and this process shows
practically the same characteristics when using both types of RXH,
indicating that this competitive pathway could potentially take
place when using RS- nucleophiles. However, the reaction times
needed for the electron transfer were much higher than the times
required for this new double RSH addition that leads to 4 (14 h
and less than 5 min for the electron transfer using ROH and the
double RSH addition, respectively). This observation indicates
that even though an electron transfer process is suitable when
using RS- nucleophiles after formation of 13, the radical RS•
addition that generates 4 takes place before any possible electron
transfer. When using ROH derivatives, no radicals seem to be
formed in the reaction media (Figure 7c) and, therefore, there are
not any viable and fast pathways competing against the electron
transfer.
Figure 5. Structure of the most favorable TS-I found with β-cis and β-trans
selectivity, including the energy of the S--I halogen bond in β-cis TS-I calculated
with NBO. Coloured surfaces in the NCIPlot[36] analysis (bottom) represent non-
covalent interactions (NCI): As the surfaces become bluer, the NCI are stronger,
and as the surfaces become yellow, the NCI are weaker.
Interestingly, the RS• addition to 7 (TS-II) is cis-specific, since
the RS group always follows the same direction (elimination
direction) to replace the IPhCO2 group (Figure 5a).[37] In order to
gain more insight into this step, we analyzed the spin densities,
Wiberg bond orders (WBO),[38] and geometries along its intrinsic
reaction coordinate (IRC) (Figure 5b). The results suggest that
this addition is a concerted process in which the second C-S bond
is formed and the C-I bond cleaves with no stable intermediate
generated before 4h. In this concerted transformation, first the C-
S bond is formed while the C=C double bond becomes a single
bond, forming a hidden intermediate.[39] Then, the C-I bond breaks
at the same time as the double bond is recovered.
Even though the first RXH addition shows similar activation
barrier and common features for RSH and ROH, the products
obtained from 13 differ in a great extent (Figure 6a). One major
difference is that when using ROH nucleophiles,[17] the process
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acting as basic additives in the first RSH addition. Under the
standard reaction conditions using Cs2CO3, the results suggest
that the rate-limiting step is the formation of RS• radicals from
RSH that takes place before the second RSH addition.
Figure 6. (a) Dihedral angles of TS-II and the hidden intermediate formed during
the second RS addition along with the elimination direction of the IPhCO2 group.
(b) WBO of the breaking C-I bond as the forming C-S bond creates throughout
the IRC of the most stable TS-II, along with the spin density of different regions
of the molecule as the TS progresses. The color intensity of the points is related
to the degree of cleavage of the C-I bond.
Conclusion
In conclusion, we have discovered unprecedented reactivity
between ethynylbenziodoxolones and thiols for the regioselective
synthesis of 1,2-dithio-1-alkenes that complements previously
reported protocols. This operationally simple methodology with
versatile functional group tolerance is demonstrated in 50
examples. Furthermore, thioglycosides are also well tolerated (5
examples, 50-85% yield). It is noteworthy that benzo-1,4-dithiins
have been realized in good yield (3 examples, 56-88% yield). This
newly developed protocol has also been applied to the gram-scale
synthesis of 1,2-dithio-1-alkenes, which are not readily accessible
by other means. Mechanistic experimental and computational
studies suggest that this reaction follows a novel reaction
mechanism between ethynylbenziodoxolones and thiols. The cis
regioselectivity observed in the final products is created through
a combination of two steps: cis-selective nucleophilic RSH
addition (TS-I) followed by a cis-specific radical RSH addition (TS-
II). Interestingly, different inorganic salts accelerate the reaction
Figure 7. (a) Reactivity observed when using RSH and ROH with Ph-EBX. (b)
Representation of the HOMO and LUMO, along with the excitation wavelengths
(λ), oscillator strength (f) and major component of the first electronic transition
of complex [13--XTol] when using pTolS__ and pMeOPhO. These parameters
were calculated using TD-DFT. In both cases, the first electronic transition
corresponds to the electron transfer taking place from RX to intermediate 13.
(c) Radical trapping experiments using pTolSH and pTolOH.
Acknowledgements
This work was supported by Colorado State University and the
National Institute of General Medical Sciences of the National
Institutes of Health under Award Number R35GM119702. The
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10.1002/chem.201904520
Chemistry - A European Journal
RESEARCH ARTICLE
Entry for the Table of Contents
RESEARCH ARTICLE
Dr. Bin Liu, Dr. Juan V. Alegre-Requena,
Prof. Robert S. Paton, Prof. Garret M.
Miyake*
Page No. – Page No.
Unconventional
Reactivity
of
Ethynylbenziodoxolone
Reagents and Thiols: Scope and
Mechanism
(EBX)
Ethynylbenziodoxolone (EBX) reagents react with thiols form 1,2-dithio-1-alkenes
with cis regiocontrol. Experimental results and density functional theory (DFT)
calculations support that cis regioselectivity observed in the final products is through
cis-selective nucleophilic RSH addition followed by a cis-specific radical RSH
addition. The process is unique to EBX reagents.
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