Mechanistic Studies of Formal Thioboration Reactions of Alkynes

Article abstract of DOI:10.1021/acs.joc.7b01500

Several formal heteroborylative cyclization reactions have been recently reported, but little physical-organic and mechanistic data are known. We now investigate the catalyst-free formal thioboration reaction of alkynes to gain mechanistic insight into B-chlorocatecholborane (ClBcat) in its new role as an alkynophilic Lewis acid in electrophilic cyclization/dealkylation reactions. In kinetic studies, the reaction is second-order globally and first-order with respect to both the 2-alkynylthioanisole substrate and the ClBcat electrophile, with activation parameters of ΔG^? = 27.1 ± 0.1 kcal mol^-1 at 90 °C, ΔH^? = 13.8 ± 1.0 kcal mol^-1, and ΔS^? = -37 ± 3 cal mol^-1 K^-1, measured over the range 70-90 °C. Carbon kinetic isotope effects supported a rate-determining Ad_E3 mechanism wherein alkyne activation by neutral ClBcat is concerted with cyclative attack by nucleophilic sulfur. A Hammett study found a ρ⁺ of -1.7, suggesting cationic charge buildup during the cyclization and supporting rate-determining concerted cyclization. Studies of the reaction with tris(pentafluorophenyl)borane (B(C₆F₅)₃), an activating agent capable of cyclization but not dealkylation, resulted in the isolation of a postcyclization zwitterionic intermediate. Kinetic studies via UV-vis spectroscopy with this boron reagent found second-order kinetics, supporting the likely relevancy of intermediates in this system to the ClBcat system. Computational studies comparing ClBcat with BCl₃ as an activating agent showed why BCl₃, in contrast to ClBcat, failed to mediate the complete the cyclization/demethylation reaction sequence by itself. Overall, the results support a mechanism in which the ClBcat reagent serves a bifunctional role by sequentially activating the alkyne, despite being less electrophilic than other known alkyne-activating reagents and then providing chloride for post-rate-determining demethylation/neutralization of the resulting zwitterionic intermediate.

Full text of DOI:10.1021/acs.joc.7b01500

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Article
Mechanistic Studies of Formal Thioboration Reactions of Alkynes
Adena Issaian, Darius J. Faizi, Johnathan O. Bailey, Peter Mayer,
Guillaume BERIONNI, Daniel A. Singleton, and Suzanne A. Blum
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01500 • Publication Date (Web): 03 Jul 2017
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The Journal of Organic Chemistry
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Mechanistic Studies of Formal Thioboration Reactions of Al-
kynes
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Adena Issaian,‡,# Darius J. Faizi,‡,# Johnathan O. Bailey,§ Peter Mayer,† Guillaume Berionni,*† Daniel
A. Singleton*§ and Suzanne A. Blum*‡
†Department of Chemistry, Ludwig Maximilian University of Munich, Munich, 80539, Germany
§Department of Chemistry, Texas A&M University, P.O. Box 30012, College Station, Texas, 77842, United States
‡Department of Chemistry, University of California, Irvine, California, 92617−2025, United States
ABSTRACT: Several formal heteroborylative cyclization reactions have been recently reported, but little physical-organic
and mechanistic data is known. We now investigate the catalyst-free formal thioboration reaction of alkynes to gain mecha-
nistic insight into B-chlorocatecholborane (ClBcat) in its new role as an alkynophilic Lewis acid in electrophilic cycliza-
tion/dealkylation reactions. In kinetic studies, the reaction is second order globally; first order with respect to both the 2-
o
alkynylthioanisole substrate and the ClBcat electrophile, with activation parameters of ΔG‡ = 27.1 ± 0.1 kcal mol−1 at 90 C,
o
ΔH‡ = 13.8 ± 1.0 kcal mol−1 and ΔS‡ = −37 ± 3 cal mol−1 K−1, measured over the range of 70–90 C. Carbon kinetic isotope
effects supported a rate-determining AdE3 mechanism wherein alkyne activation by neutral ClBcat is concerted with cycla-
tive attack by nucleophilic sulfur. A Hammett study found a ρ+ of −1.7, suggesting cationic charge buildup during the cycliza-
tion and supporting rate-determining concerted cyclization. Studies of the reaction with tris(pentafluorophenyl)borane
(B(C6F5)3), an activating agent capable of cyclization but not dealkylation, resulted in the isolation of a post-cyclization zwit-
terionic intermediate. Kinetic studies via UV-vis spectroscopy with this boron reagent found second order kinetics, support-
ing the likely relevancy of intermediates in this system to the ClBcat system. Computational studies comparing ClBcat with
BCl3 as an activating agent showed why BCl3, in contrast to ClBcat, failed to mediate the complete the cycliza-
tion/demethylation reaction sequence by itself. Overall, the results support a mechanism in which the ClBcat reagent serves
a bifunctional role by sequentially activating the alkyne, despite being less electrophilic than other known alkyne-activating
reagents, then providing chloride for post-rate-determining demethylation/neutralization of the resulting zwitterionic
intermediate.
INTRODUCTION
Addition of boron/sulfur, boron/oxygen, and bo-
ron/nitrogen formal equivalents to C–C π bonds is an un-
der-applied area of methodology, despite its promising
efficiency in the synthesis of synthetically and biologically
useful heterocycles. Substantial recent work has shown
that the highly electrophilic B(C6F5)3 can activate alkynes
towards nucleophilic cyclization.1–4 The resulting zwitteri-
onic heterocycles, however, contain a carbon–B(C6F5)3
bond, which is unreactive for the rich downstream Suzuki
cross-coupling reactivity of boron (example, Figure 1a3).
This limits their utility as synthetic building blocks. The
development of methods that effect boron/heteroatom
additions while retaining the synthetic versatility of boron
would thus be of high impact. We recently reported that
the commercially available B-chlorocatecholborane
(ClBcat) effects boron/oxygen and boron/sulfur heterocy-
clizations,5,6 and Fu extended this methodology to bo-
ron/nitrogen heterocyclization7 (Figure 1b). Subsequently,
Ingleson found that BCl3 was sufficiently electrophilic to
bring about oxyboration and thioboration reactions of
alkynes at 20 °C, albeit with additional reagents to pro-
Figure 1. Previous work on catalyst-free borylative cycli-
mote thioboration (Figure 1c).8,9
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zations and this work on mechanistic elucidation of the
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thioboration reaction.
Scheme 1. Two Possible Mechanistic Pathways for Thioboration with ClBcat
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In the reactions with ClBcat, we hypothesized that the
reagent is bifunctional, first serving as an electrophile to
activate the alkyne and second as a source of nucleophilic
chloride that demethylates the resulting zwitterion
(Scheme 1). This two-step process produces a neutral
heterocyclic boron building block primed for subsequent
cross-coupling and other synthetically useful reactivity.
The success of the ClBcat reagent was surprising in light
of the substantially attenuated electrophilicity of ClBcat
when compared to the previously reported B(C6F5)3. The
demethylation in the BCl3 reactions of Ingleson proceed-
ed without intervention for oxygen nucleophiles. Sulfur
nucleophiles, however, required addition of stoichio-
metric AlCl3 as a Lewis acid and Et3N as a Lewis base in
order to induce chloride release and demethylation, ul-
timately forming [Et3NCH3][AlCl4]. It appears that the
balance between the boron reagent’s electrophiliciy and
its ability to later dissociate chloride is key to the devel-
opment of a wider family of reactions that access neutral
rather than zwitterionic final borylated heterocyles.
Carbophilic Lewis Acid Activation Mechanistic Pro-
posal. The mechanistic pathways considered here for the
cyclative thioboration reaction are shown in Scheme 1.
Both of these possible reaction routes take advantage of
Lewis acidic boron-induced activation of the alkyne in
thioanisole 1 to generate zwitterionic intermediate 4.
Previous experiments ruled out alternative mechanistic
pathways that proceed through either B–S σ-bond for-
mation/cyclization or haloboration/cyclization routes
when ClBcat is the boron electrophile.6
The mechanism in Scheme 1 uses monomeric neutral
ClBcat as the electrophile, but this was not clear at the
beginning of our studies. It also disregards the possible
involvement of an alkyne–ClBcat π-complex intermedi-
ate. With these simplifications to be evaluated later, a
central mechanistic question was whether the addition
occurs by a two-step process through vinyl cation inter-
mediate 2 (Scheme 1, top pathway),10 or by a concerted
AdE3 addition (formally AdE2, wherein the nucleophilie is
intramolecular) via transition state (TS) 3 (Scheme 1,
bottom pathway).11 Qualitatively, it might be anticipated
that the choice between mechanisms would depend on
the strength of the electrophile; weak electrophiles might
be unable to generate the vinyl cation (top) but still ac-
complish the AdE3 addition (bottom).
These observations open the possibility of a suite of re-
lated new reactions employing related boron reagents
that may have been previously dismissed as insufficiently
electrophilic to effect borylative heterocylizations. Press-
ing mechanistic questions arise, the answers to which
will facilitate the development of optimal reagents for
synthetically useful transformations: What is the nature
of activation of the alkyne given the lower electrophilicity
of ClBcat (and is this nature nevertheless similar to the
previously used reagent B(C6F5)3), what are the struc-
tures and the reactivities of the reaction intermediates,
and how do different reagents compare? Here, we pre-
sent a comprehensive study into ClBcat-induced cyclative
thioboration to answer these questions. The results pro-
vide guiding principles for developing related borylative
cyclization/dealkylation reactions.
In both pathways, 4 is then demethylated by chloride
ion, either via ion pair 5 or by a boron-based chloride
shuttle.7 The demethylation yields the final 3-borylated-
benzothiophene product 6. Both pathways show the key
bifunctional reactivity of ClBcat, first as an electrophilic
activating agent and second as a source of nucleophilic
chloride.
Kinetic Studies. For the first set of kinetic experi-
ments, substrate 1a was treated with ClBcat. The reac-
o
tion was run at 90 C and at 0.05–0.20 M in substrate in
toluene-d8 to allow for the monitoring of the initial reac-
tion rates by 1H NMR spectroscopy using mesitylene as
an internal standard. Initial rates were measured over a
3%–8% range of product yield for all conditions. Stand-
RESULTS AND DISCUSSION
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ard deviations are reported from triplicate runs. Genera- The results are summarized in Figure 2. The KIEs at
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4
5
6
7
8
tion of 6a exhibited a first-order kinetic dependence with
respect to the substrate concentration and a first-order
kinetic dependence with respect to ClBcat (Table 1). The
reaction exhibited second-order kinetics overall. This
dependence on both components rules out a rate-
determining preactivition step of the ClBcat (e.g., to gen-
erate a borenium12), thus, the active carbophilic Lewis
acid in this system is assigned as ClBcat.
the arene carbons are all negligible, while a very small
KIE is observed at the methylthio carbon. The key obser-
vation is that both alkynyl carbons exhibit a significant
13C KIE. The qualitative interpretation of these KIEs is
that both alkynyl carbons are undergoing bonding
changes in the rate-limiting TS, as would fit with an AdE3
mechanism, and the substantial KIE at the external al-
kynyl carbon appears inconsistent with rate-limiting
electrophilic addition to form 2. A more quantitative
interpretation will be possible with the aid of computa-
tional studies (vide infra).
9
Eyring Analysis. Additional insight into the mechanism
was obtained by an Eyring analysis of the rate constants
over a 70–90 °C temperature range. Incorporating the
observed bimolecular kinetics, the rate constants k at
each temperature were obtained by dividing kobs by the
concentration of the reactants. Plotting ln (k/T) versus
1/T yields a ΔH‡ of 13.8 ± 1.0 kcal mol−1 and a ΔS‡ of −37
± 3 cal mol−1 K−1, with ΔG‡ at 90 °C being 27.1 ± 0.1 kcal
mol−1. The substantially negative ΔS‡ is in a normal range
for a bimolecular association reaction with no release of
a free molecule (such as Cl–) prior to the rate-limiting
step.13
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Table 1. Observed Reaction Rate Constants at Varying
Concentrations and Temperaturesa
Figure
2.
Experimental
and
B3LYP-D3/6-31+G**/PCM(toluene)-predicted
(italicized
and in brackets) 13C KIEs (k12/k13) at 85 °C for the thiobora-
tion reaction of 1a with ClBcat. The 95% confidence limits
on the last digit are shown in parentheses with the experi-
mental values.
Substituent Effects. A Hammett study was conducted
to assess the charge buildup in the TS at the external
alkynyl carbon. The relative reaction rates of para-
substituted arylalkynylthioanisole derivatives (1 with R
= p-C6H4X) were assessed via competition experiments in
which a solution of ClBcat was added to a solution of 3.0
equiv of a para-substituted alkynylthioanisole and 3.0
equiv of a differently substituted alkynylthioanisole in
toluene-d8 (Figure 3). These reactions were monitored by
1H NMR spectroscopy using mesitylene as an internal
standard and found to be complete in 2–4 h. The product
ratios did not change upon standing.
Entry
Equiv (1a) Equiv (ClBcat) T (oC)
Rate (10-6 M s-1)
6.5 0.5
1
2
3
4
5
6
7
2.0
0.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
0.5
1.0
1.0
1.0
90
90
90
90
90
80
70
1.8 0.2
8.0 0.1
2.0 0.3
3.7 0.2
1.8 0.1
1.1 0.1
aAs an example, absolute concentration in entry 5 was 0.1
4
M 1a and 0.1 M ClBcat in toluene-d8.
-2
-1.5
NMe2
-1
-0.5
0
0.5
1
3
2
Carbon Kinetic Isotope Effects. The 13C kinetic iso-
tope effects (KIEs) for the reaction of 1a with ClBcat
were determined at natural abundance by NMR method-
ology.14 Independent reactions of 1a with ClBcat at 85 °C
in toluene were taken to 74% and 75% conversions, and
the unreacted 1a was reisolated by chromatography after
a normal workup. The change in the isotopic composition
of 1a was determined by analysis of its 13C NMR spec-
trum in comparison with 1a from the same synthetic lot
that had not been subjected to the reaction conditions.
The arene carbon para to the alkynyl group was used as
an internal standard for the NMR integrations with the
assumption that isotopic fractionation in this position is
negligible. From the changes in the isotopic composition
at each position and the conversions of the reactions, the
KIEs were calculated as previously described.
1
OMe
Br
Me
0
CO2Me
CF3
F
Cl
+
ρ = –1.7
R² = 0.993
-1
-2
+
σ
Figure 3. Hammett study showing correlation between
log(k/ko) and σ+ at 100 °C.
A variety of substituents were tested that encompassed
the range of electronic possibilities, including electron-
withdrawing (p-CF3, p-CO2Me), slightly donating (p-F and
p-Me), and strongly donating (p-NMe2, p-OMe) substitu-
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ents. The product ratios obtained through this series of
Page 4 of 17
competition experiments were then potted against σ+
and σp. A better fit was obtained when the log of the rela-
tive reaction rates were plotted against σ+ (R2 = 0.993)
than against σp (R2 = 0.957), providing a ρ+ value of –1.7
(Figure 3). The negative slope indicates that there is
positive charge buildup at the external alkynyl carbon in
the rate-determining step, and this could not happen
unless electrophilic attack by the boron on the internal
alkynyl carbon had progressed substantially.
1
2
3
4
5
6
7
8
Table 2. Varying the Substituent Position
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We next considered the magnitude of the ρ+ value, in
order to assess if the rate-determining step involved
formation of a formal vinylic cation (top pathway) or a
simultaneous boron activation-sulfur ring-closing event
to form the sulfonium species (bottom pathway). The low
absolute value of ρ+ suggests that electronic resonance
stabilization effects are not as significant as those seen in
systems involving the discrete formation of resonance-
stabilized carbocations. The ρ+ values for reactions that
generate benzylic carbocations are typically greater than
4.0.15,16 Assuming that an addition of the ClBcat electro-
phile to afford vinyl cation 2 would involve a late TS, as
expected from Hammond’s postulate, a similarly large ρ+
would be expected for the vinyl cation mechanism (top
pathway). The ρ+ value of –1.7 is then more consistent
with the AdE3 mechanism, in agreement with the isotope
effects.
Entry
R Group
o-Cl
Yield (%)a 6b
1
2
3
4
5
6
57
54
73
85
89
88
3
3
1
2
3
1
m-Cl
p-Cl
o-Me
m-Me
p-Me
aError is reported as standard deviation of two runs.
Nucleophilicity and Heteroatom Competition Ex-
periments. To gain additional insight about the thiobo-
ration reaction, a series of competition experiments were
conducted. The effects of nucleophilicity and conforma-
tional bias were analyzed by comparing the relative reac-
tion rates of alkynylthioanisole 1a and alkynylthioether 7
via an intermolecular competition experiment. A solution
of ClBcat (1.0 equiv) was added to a solution of 1a and 7
(3.0 equiv each) in toluene-d8 (eq 1). The reaction was
monitored by 1H NMR spectroscopy at t = 2 h and 4 h,
using mesitylene as an internal standard.
1H NMR spectroscopic analysis at t = 2 h showed that
the relative yields of 6a and 8 were 7% and 62%, respec-
tively, relative to the limiting ClBcat reagent. Examina-
tion at 4 h showed that the product ratios did not change
significantly upon standing. The disfavorable formation
of 6a compared to 8 may be due to withdrawal of elec-
tron density from sulfur by the phenyl ring in 1a, which
reduces its nucleophilicity and makes it less favorable to
attack the alkyne in comparison with the more nucleo-
philic sulfur in compound 7. Thus, the enhanced nucleo-
philicity of the thioether in 7 outweighs the conforma-
tional bias towards cyclization of rigid 1a.
The substituent location was next varied on the phenyl
ring to probe effects on rate of cyclization in the thiobo-
ration reaction (Table 2). Two substituents (R = Me, Cl)
were selected to incorporate both a moderate electron-
donating group and a moderate electron-withdrawing
group. These 2-alkynylthioanisole derivatives (1) were
subjected to standard thioboration conditions (1.3 M
toluene-d8 with respect to starting material, 1.4 equiv
ClBcat, 100 oC) and examined by 1H NMR spectroscopy at
t = 2 h using mesitylene as an internal standard. Each
reaction was run in duplicate and yields are reported
with the standard deviation of two runs.
If sterics were the dominating factor on rate of the thi-
oboration reaction, then ortho-substituted phenyl rings
would result in lower yields at a given reaction time.
When R = Me, however, all three substitution patterns
provided statistically comparable yields (~82%). This
indicates a minimal steric influence in this system or one
that is exactly balanced by electronics. When R = Cl, the
1
p-Cl provided the highest H NMR yield (73 ± 1%), and
both o-Cl and m-Cl provided comparable yields (57 ± 3%
and 54 ± 3%, respectively). The higher yield with p-Cl
versus m-Cl is likely due to the lower σ+ value of p-Cl due
to its resonance donation. A balance of electronegativity
and resonance donation can account for the similar
yields obtained with ortho-chloro and meta-chloro. The
σ+ of o-Cl is not defined, but the electron-withdrawing
effects of ortho halogens are greatly enhanced versus the
meta and para positions (the pKa of o-chlorobenzoic acid
is 2.92 versus 3.82 for m-chlorobenzoic acid17), so the
electronic withdrawing ability of o-Cl can be balanced by
some resonance donation. These observations are con-
sistent with the importance of stabilizing positive charge
at the benzylic position.
In order to examine the nature of the initial alkyne ac-
tivation step by ClBcat, we next examined an intermolec-
ular competition reaction between thioboration and
oxyboration, starting from substrate 1b. Starting materi-
al 1b was added to a solution of ClBcat (1.4 equiv) in
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toluene-d8 (eq 2) with mesitylene as an internal standard. 1c, depending on whether the Bcat group is anti to the
The reaction was monitored for the formation of prod-
‡
SCH3 group (3canti‡) or syn to the SCH3 group (3csyn
)
1
2
3
4
5
6
7
8
1
ucts 6b and 9 by H NMR spectroscopy over 2–24 h. At t
(Scheme 2). The free-energy barriers associated with
these VTSs using a 1 M standard state are 25.4 kcal/mol,
in good agreement with the experimental barriers. This is
somewhat misleading because the calculated barriers
have not allowed for the entropy of symmetry of the
ClBcat, the entropy of mixing of the chiral VTSs, and the
kinetic combination of the two VTSs. Together these
factors increase the rate by a factor of ~8, lowering the
predicted barrier by 1.5 kcal/mol. The phenomenological
entropy of activation was calculated from the summed
SCT rate constants at 70 and 90 °C, allowing for a 1.0 M
standard state and the entropies of mixing and sym-
metry, giving a ꢀS‡ of –37.4 e.u. matching the experi-
mental value. We note that the inclusion of arbitrary
entropy “corrections” often employed in the literature22
would have led to poor predictions of both the free ener-
gy barrier and the entropy of activation.
= 2 h the ratio of 6b to 9 was 4.2:1.0. This ratio remains
approximately the same at t = 4 h, but the ratio at longer
reaction times could not be determined due to apparent
product decomposition.
This data shows a slight preference for thioboration
over oxyboration corresponding to ∆∆G‡ = 1.1 kcal/mol
at 373 K. The similarity in reaction barriers suggests that
alkyne activation (plausibly relatively similar for either
heterocyclization since the same alkyne is activated) is
the dominant contributor to the barrier, rather than the
nucleophilic attack (plausibly substantially different for
carboxy versus thio since the nature of the attacking
nucleophile is different). This suggests that boron–
carbon bond formation is more advanced at the TS than
carbon–nucleophile bond formation, as would be con-
sistent with the Hammett study. The consistency of this
idea with the 13C KIEs is assessed with the aid of compu-
tations (vide infra). These results align with the previous
observations by Larock, which showed that the cycliza-
tion selectivity for SMe vs. COOMe in this substrate is
electrophile dependent.18
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Scheme 2. Calculated mechanism (B3LYP-D3/6-
31+G**/PCM(toluene)) for the reaction of 1c with
ClBcat.
O
S
O
ClBcat
(1.4 equiv)
Bcat
S
(2)
toluene-d8
100 o
S
O
C
Bcat
O
O
O
6b-xiii
9
oxyboration
1.0
thioboration
4.2
1b-xiii
t = 2 h
:
Computational Study of the ClBcat Reaction. The
reaction of ClBcat with 1c was studied with DFT calcula-
tions. A series of DFT method and basis set combinations
were explored (see SI). Each predicted the same overall
mechanism but with some significant variation in the TS
geometries. Ordinarily, it would be desirable to choose
among the methods based on high-level ab initio bench-
marking for a tractable simplified reaction model, but the
complexity of the reaction leaves us without a satisfacto-
ry small model. We will describe here the results of
B3LYP/6-31+G** calculations including a PCM solvent
model and Grimme’s D3 dispersion corrections, then
discuss how the predictions of other methods differ.
A second complication in the current reaction is that
the key potential energy saddle points (the conventional
TSs) for the AdE3 addition of ClBcat to 1c lie in relatively
flat regions of the energy surface where there is also a
relatively rapid decrease in the entropy along the reac-
tion coordinate. When this happens, conventional transi-
tion state theory (TST) is subject to significant error. It is
then better to use canonical variational transition states
(VTSs), i.e. free-energy maxima instead of potential-
energy maxima, to predict rates and isotope effects. VTSs
were located here using GAUSSRATE / POLYRATE,19,20
and they are later than the conventional TSs. For the rate
constants associated with the VTSs, tunneling was in-
cluded using the small-curvature tunneling (SCT) ap-
proximation.21
In 3canti‡ and 3csyn‡, the bonding between the boron and
the internal alkynyl carbon is very advanced while bond-
ing between the sulfur and the external alkynyl carbon
has progressed to a much lower extent. The external
alkynyl carbon is then moving more at the VTS, and this
fits with the larger KIE observed at this carbon. The dif-
Two AdE3 VTSs of approximately equal energy (within
0.1 kcal/mol) were located for the addition of ClBcat to
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ferent degrees of bonding at the two carbons in the VTS pass a relatively large range, from 1.007 to 1.011 and
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8
also leads to a partial positive charge at the external
alkynyl carbon in the VTS, with a gain in charge of 0.63 in
Mulliken-charge calculations. This is consistent with the
negative ρ+ seen in the Hammett study.
from 1.013 to 1.029 at the internal and external alkynyl
carbons, respectively. Because there is no independent
way to choose among DFT methods in the current reac-
tion, it would not be correct to say that calculations were
able to “predict” the experimental KIEs with good preci-
sion. However, it is clear that the experimental KIEs are
consistent with the AdE3 mechanism. Considering this,
along with the consistency of the calculated barrier, en-
tropy, molecularity, and charges with diverse experi-
mental observations, the combination of experiment and
computations strongly supports the AdE3 addition.
The two AdE3 VTSs lead to conformational isomers
4canti and 4csyn. The chloride in these zwitterionic hetero-
cycles is predicted to remain bound to the boron; at-
tempts to locate simple ion pairs by dissociating the chlo-
ride led back to the 4c on optimization. The 4c adducts
are uphill from the reactants but they do not go back-
ward because they face a low barrier to their SN2 de-
methylation via TS 10‡ to afford the neutral product 6.
The AdE3 addition is thus predicted to be the rate-
determining step in the reaction.
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Computational Study of the BCl3 Reaction. In the re-
action of BCl3 with 1b (R = phenyl), Ingleson observed by
NMR spectroscopy a zwitterionic product that was as-
signed as having structure 11 (eq 3).9 Unlike our pro-
posed intermediate 4, 11 did not spontaneously demeth-
ylate. Instead, the neutral product 12 was produced after
sequential treatment with Et3N for demethylation and
AlCl3 to remove the chloride. It was of interest to under-
stand why BCl3 failed to adopt a bifunctional role in this
reaction while ClBcat mediates the complete conversion
by itself.
A series of alternative mechanistic possibilities were
explored. No TS could be located for an addition of ClBcat
to 1c without concomitant nucleophilic attack by the
methylthio group. Attempts to optimize the vinyl cation 2
led to C–S bond formation to afford 4canti or 4csyn. The
AdE3 process in the presence of a second molecule of
ClBcat was explored with the idea that coordination to
the chloride could enhance the reactivity of the electro-
‡
CH3
phile. A structure analogous to 3csyn but with a second
S
Et3N
S
S
BCl3
CH3
ClBcat was located, but it was 3.7 kcal/mol higher in
energy. This fits with the experimental kinetics that were
unimolecular in ClBcat. Finally, we considered the possi-
ble role of an alkyne–boron π-complex as a precursor to
the AdE3 addition step. A series of loose molecular com-
plexes of 1c were located, the most stable of which
placed the S atom of 1c in loose coordination with the B
atom of the ClBcat. This loose coordination to sulfur was
in agreement with weak charge-transfer bands observed
at a low temperature in the UV-vis spectrum with large
excess of ClBcat (see SI for details). All of the complexes
were higher in free-energy than separate starting mate-
rials and as a result are not of kinetic significance in the
mechanism.
(eq 3)
Ph
Ph
then
AlCl3
20 °C
BCl3
11
BCl2
12
Ph
1b
To examine this issue, the reaction of BCl3 with 1c was
investigated computationally. BCl3 is a much stronger
electrophile than ClBcat and this is reflected in its low
reaction temperature with 1b. The B3LYP-D3 calcula-
tions mirror this observation, predicting the barrier at
25 °C to be only 18.0 kcal/mol. The TS 13‡ for the addi-
‡
tion is much earlier than the corresponding 3canti and
3csyn TSs with ClBcat, and only the single TS could be
‡
located. The C–S distance for the ring-closing bond in 13‡
is so long, at 3.22 Å, that the involvement of the sulfur
atom as a nucleophile is nearly negligible, but no step-
wise intermediate before the cyclized product 14 could
be located.
Predicted KIEs. The prediction of the 13C KIEs for VTSs
‡
‡
3canti and 3csyn could in principle be based on the SCT
rate constants, but in practice this requires that
POLYRATE rate constants be numerically converged to 4
significant figures (requiring long paths and very small
steps along the path) to allow their comparison for KIE
calculations. This was judged impractical, so an alterna-
tive process of applying the method of Bigeleisen and
Mayer23–25 (designed for TST) to the VTSs was employed.
One-dimensional tunneling corrections26 to the 13C KIEs
were negligible (<0.0003) so it was expected that the
inclusion of SCT in the KIEs would be unimportant.
The results are summarized alongside the experi-
mental KIEs in Figure 2. The agreement is very good, in
that the predicted isotope effects fit well the pattern of
isotope effects seen experimentally. However, there is a
problem that compromises the significance of this
agreement. As alluded to earlier, the geometry of the
AdE3 transition states varies significantly across a series
of calculations (see the SI for details). The forming C–B
interatomic distances in the TSs range from 1.86 to 2.13
while the C–S distance varies from 2.70 to 2.96. The effect
of this variation is that the predicted KIEs also encom-
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Scheme 3. Two Possible Mechanisms for Thioboration with B(C6F5)3 and Isolation of Intermediates
5
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To proceed on to the neutral product 16 without assis-
tance from additional reagents, a chloride anion would
have to dissociate then effect the demethylation via SN2
TS 15‡. The free energy of 15‡ is only modestly above 13‡
but its starting point, 14, is more stable, so the barrier for
demethylation of 14 once formed is 4.9 kcal/mol higher
than the original barrier for its formation. In this way, the
high electrophilicity of the BCl3 works against the overall
conversion by making the intermediate zwitterion too
stable.
The formation of the zwitterion 19 was monitored by
time-resolved UV–vis spectrophotometry at its maximum
absorption (λmax = 317 nm) in CH2Cl2 at 20 °C under
pseudo-first conditions (large excess of B(C6F5)3, see SI).
These kinetic experiments showed that the reaction is
first order with respect to both 1d and B(C6F5)3, thus
following an overall second-order behavior with a se-
cond-order rate constant of k = 2.00 × 10–1 mol L–1 s–1
(ΔG‡ = 18.1 kcal/mol at 293 K).
The 11B NMR spectrum of the zwitterion 19 showed a
singlet at δ = –14.7 ppm, in agreement with previously
reported chromone and indole derivatives.28,29 The com-
plex 19F NMR spectrum of 19 indicated that the rotation
around the C–B bond was restricted. Additionally, the
These results qualitatively account for Ingleson’s ob-
servations, but the calculated barrier for the demethyla-
tion of 14, 22.9 kcal/mol, is quantitatively too low by ~2
kcal/mol. It should be recognized however that DFT
calculations tend to underestimate the stability of dative
bonds to boron in ate complexes by several kcal/mol,27
and this would fit with the small discrepancy.
1
presence of two sets of signals in the H, 19F and 13C NMR
revealed that 19 existed in solution as two diastereomer-
ic conformations with a 65:35 ratio according to the
Characterization of Intermediates. In order to inves-
tigate reaction intermediates and their fundamental
reactivity, as well as to determine how ClBcat compared
as a carbophilic electrophile to the previously used highly
electrophilic reagent tris(pentafluorophenyl)borane
(B(C6F5)3), we treated the 2-alkynyl thioanisole substrate
1d with 1.0 equivalent of B(C6F5)3. Notably, this reagent
has the potential to display similar reactivity to ClBcat in
the initial alkyne activation step, but lacks the bifunc-
tional ability to dissociate an anionic ligand and thus
lacks the ability to induce subsequent demethylation.
Thus, this reagent may permit “freezing” of the reaction
pathway at zwitterionic intermediate 19,9 which in turn
would permit the study of its structure and of its funda-
mental reactivity independent of the borylative hetero-
cyclization step. Indeed, after 1 h at 20 oC in CH2Cl2 the 1-
methyl-1-benzothiophenium borate intermediate 19 was
isolated in 81% yield (Scheme 3).
1
integrals of the H NMR spectroscopy signals of the two
inequivalent S+–Me groups at 3.08 and 2.90 ppm, respec-
tively. This observation was consistent with restricted
bond rotation on the 1H NMR spectroscopy timescale,
likely around the C–B bond connecting the B(C6F5)3
group to the benzothiophene core, consistent with the
steric crowding observed around the C3-B bond in the
crystal structure (Figure 4). This assignment of the origin
of restricted rotation is consistent with full lack of sym-
metry displayed in the 19F NMR spectrum and with pre-
vious reports.29 This ratio was solvent (CD3CN, CD2Cl2,
DMSO-d6) and temperature independent (in CD3CN) in
1
the range – 40 to + 40 °C). As the H-1H NOESY experi-
ments in CD2Cl2 at 20 °C (mixing time up to 1000 ms)
remained inconclusive, the relative configuration and full
signal attribution for both diastereomers was not at-
tempted. Single-crystal X-ray diffraction analysis, howev-
er, unambiguously confirmed the solid-state structure of
intermediate 19 (Figure 4).
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Carbon KIE studies and the magnitude of the ρ+ from
1
the Hammett study both indicated a concerted cycliza-
tion with ClBcat. To gauge, in contrast, if the more elec-
trophilic B(C6F5)3 was sufficiently more reactive to access
a formal cation, this reagent was next investigated. When
1d was reacted with the frustrated Lewis pair
(C6F5)3B/(o-tolyl)3P (Scheme 4), the phosphine-boration
product 21 or its regioisomer 22 were not observed, and
20 was formed exclusively. This data suggests that the
cyclization pathway is concerted even with this more
electrophilic reagent, since an intermediate short-lived
vinyl-cation (17 or its regioisomer), of high electrophilic-
ity,30 might at least be partially trapped by the phosphine
(o-tolyl)3P. The phosphine is significantly more nucleo-
philic in comparison to the sulfur atom in the –SMe ortho
substituent as characterized through Mayr nucleophilici-
ty studies, though zwitterion 17 may present a more
hindered approach for the bulky phosphine than the
standard Mayr substrates31,32 Thus, the AdE3 mechanism
herein characterized for ClBcat-induced thioboration
appears to operate even for this more highly electrophilic
boron reagent (Scheme 1, Step C).
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Figure 4. X-ray structure (ellipsoids shown at the 50%
probability level) of 19. Selected interatomic distances (Å)
and angles (deg): S1–C2 = 1.805(1), C2–C3 = 1.357(2), C3–
B1 = 1.645(2), C3–C9 = 1.483(2), C9–C8 = 1.405(2), C8–S1 =
1.754(1), S1–C1 = 1.805(1), C8–S1–C2 = 92.56(6), S1–C2–C3
= 111.43(9).
Scheme 4. Reaction of 1c with the FLP
(C6F5)3B/(o-tolyl)3P at 20 °C in CH2Cl2.
The next question was whether now-characterized in-
termediate 19 was relevant and analogous to the pro-
posed but undetected zwitterionic intermediate 4 de-
rived from ClBcat-induced borylative heterocyclization.
Intermediate 4 could not be detected under our condi-
tions, presumably due to its location on the reaction
energy surface after rate-determining borylative hetero-
cyclization. To investigate this hypothesis, the reactivity
of 19 towards demethlation by chloride was investigated
and found to be not only feasible but markedly fast at
ambient temperature. This is the analogous demethyla-
tion reactivity proposed for unobserved 4 (either direct
or via neutral 5). Specifically, multinuclear NMR spectro-
scopic monitoring of the demethylation of 19 by various
nucleophiles (o-tolyl)3P, DMSO and Me4N+Cl–) was per-
formed. Whereas demethylation occurred slowly either
with (o-tolyl)3P or DMSO-d6 (Scheme 3, top/middle), it
proceeded immediately with Et4N+Cl (Scheme 3, bottom)
to provide 20 in high yield. A crystal structure of 20 was
obtained for full characterization and confirmed the
formation of this product (See SI).
S
B(C6F5)3
or
regioisomer
P(o-tolyl)3
P(o-tolyl)3
S
S
B(C6F5)3
21
22
not observed
B(C6F5)3
20
> 90%
1d
17
CONCLUSIONS
Thioborylative cyclization reactions with three differ-
ent boron electrophiles, ClBcat, BCl3, and B(C6F5)3 were
investigated by a combined experimental and computa-
tional approach. With ClBcat: Hammett studies indicate a
concerted reaction pathway, kinetic studies show a bimo-
lecular rate-determining step, 13C KIE studies support a
rate-determining AdE3 mechanism, competition experi-
ments suggest the involvement of sulfur as a nucleophile
in the rate-determining step, and DFT studies indicate
that a low barrier chloride dissociation enables the rea-
gent to perform the subsequent demethylation in the
absence of added reagents. With BCl3 in contrast, DFT
studies indicate a higher barrier chloride dissociation
that qualitatively accounts for Ingleson's observation8
that additional reagents are required to promote de-
methylation. With B(C6F5)3, a methylated zwitterionic
reaction intermediate was isolated and characterized by
Demethylation by chloride was sufficiently fast that
zwitterion 19 was already fully demethylated after mix-
ing with Me4N+Cl– and immediate recording of the 1H
NMR spectrum (< 1 min). The simultaneous formation of
1
CH3Cl was confirmed by H and 13C NMR spectroscopy (δ
1H = 3.03 ppm, δ 13C = 26.0 ppm). Thus, chloride is par-
ticularly well-suited for rapid demethylation, supporting
demethylation of 4 or 5 to 6 (Scheme 1, Step E) and sup-
porting a bifunctional role for ClBcat as both an alkyne
activator and chloride source for post-cyclization de-
methylation in the synthesis of neutral organoboron
building blocks. This observation also shows that free
chloride, when and if present, is a rapid demethylation
agent. This point is consistent with the previous conclu-
sion that the higher electrophilicity of the BCl3 unit in
zwitterion 11 is preventing demethylation of this zwit-
terion in the absence of additional reagents.
9
X-ray crystallography, and similar to BCl3, it required
additives for demethylation. With B(C6F5)3, UV-vis kinet-
ics demonstrated a bimolecular rate-determining step,
and trapping experiments did not support the formation
of a long-lived vinyl carbocation despite this reagent's
high electrophilicity.
Together, these observations indicate that the com-
mercially available reagent ClBcat serves a bifunctional
role as both an electrophilic alkyne activator and a nucle-
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ophilic chloride source for demethylation. The alkyne- were based on additional 2D-NMR spectroscopy experi-
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activation/cyclization process is concerted and rate-
determining, followed by rapid demethylation by re-
leased chloride. These conclusions are significant for
reaction design and improvement because they suggest
that increasing the electrophilicity of the boron reagent
while keeping its bifunctional ability to release a nucleo-
phile for dealkylation is the key needed feature. This
bifunctional reactivity requires a balance of electrophlici-
ty at boron: sufficiently electrophilic to activate the al-
kyne but insufficiently electrophilic to prevent decoordi-
nation of the chloride after alkyne activation. Although
less electrophilic than previously reported boron rea-
gents for heteroborylative cyclization reactions, ClBcat is
sufficiently electrophilic to participate in the AdE3 mech-
anism. These outcomes provide direction for reaction
design through understanding the fundamental reactivity
of ClBcat—and by extension, other practical, readily
available, and synthetically useful boron reagents—
towards alkynes in electrophilic borylation reactions that
produce functionalizable organoboron building blocks
primed for downstream reactivity.
ments (COSY, HSQC and HMBC). HRMS ESI mode were
performed on a LTQ mass spectrometer and in FAB mode
with a Jeol MStation dual focusing sector field mass spec-
trometer at Ludwig Maximilian University of Munich or
at the mass spectroscopy facility at the University of
California, Irvine. Melting points were determined on a
Büchi B-540 device on capillary tubes and are not cor-
rected. Infrared (IR) spectra of neat compounds were
recorded on an IR spectrometer (Spectrum BX from Per-
kin Elmer) with an ATR unit (attenuated total reflection;
Dura Sampler Diamond ATR from Smiths Detection) at
Ludwig Maximilian University of Munich.
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Trimethyl((2-(methylthio)phenyl)ethynyl)silane (SI-1).
Trimethyl((2-(methylthio)phenyl)ethynyl)silane
was
synthesized using a literature procedure34 in 98% yield.
1H NMR (CDCl3, 600 MHz): δ 7.42 (dd, J = 7.6, 0.2 Hz, 1H),
7.27 (td, J = 8.0, 1.5 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 7.06
(td, J = 7.6, 1.1 Hz, 1H), 2.48 (s, 3H), 0.30 (s, 9H). This
spectrum is in agreement with previously reported spec-
tral data.34
EXPERIMENTAL SECTION
General Information. All chemicals were used as re-
ceived from commercial sources unless otherwise noted.
Triethylamine, acetonitrile, toluene and tetrahydrofuran
were purified by passage through an alumina column
under argon pressure on a push-still solvent system.
Dichloromethane was freshly distilled over CaH2 prior to
use. Et2O was distilled over sodium/benzophenone. Tol-
uene-d8 was dried over CaH2, degassed using three
freeze-pump-thaw cycles, and vacuum transferred prior
to use. All manipulations were conducted using standard
Schlenk techniques unless otherwise specified. Analytical
thin layer chromatography (TLC) was performed using
Merck F250 plates. Plates were visualized under UV irra-
diation (254 nm) and/or using a basic aqueous solution
of potassium permanganate. Flash chromatography was
conducted using a Teledyne Isco Combiflash® Rf 200
Automated Flash Chromatography System, and Teledyne
Isco Redisep® 35–70 µm silica gel. All proton, carbon,
fluorine, boron and phosphorus nuclear magnetic reso-
nance (1H, 13C, 19F, 11B and 31P NMR) spectra were rec-
orded on a Bruker DRX-500 spectrometer outfitted with
a cryoprobe, or a Bruker AVANCE-600 spectrometer
outfitted with a cryoprobe, or Varian NMR spectrome-
ters. All chemical shifts (δ) are reported in parts per mil-
lion (ppm) downfield of tetramethylsilane, and refer-
enced to the residual protiated solvent peak (δH = 7.26
ppm for CDCl3, δH = 1.94 ppm for CD3CN, δH = 5.32 ppm
(2-Ethynylphenyl)(methyl)sulfane
(SI-2).
(2-
Ethynylphenyl)(methyl)sulfane was synthesized using a
1
literature procedure34 in 99% yield. H NMR (CDCl3, 600
MHz): δ 7.46 (d, J = 7.6 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H),
7.16 (d, J = 8.0 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 3.48 (s,
1H), 2.49 (s, 3H). This spectrum is in agreement with
previously reported spectral data.34
(2-((4-Chlorophenyl)ethynyl)phenyl)(methyl)sulfane
(1b-i).
(2-((4-
Chlorophenyl)ethynyl)phenyl)(methyl)sulfane was syn-
1
thesized using a literature procedure34 in 99% yield. H
NMR (CDCl3, 600 MHz): δ 7.50 (d, J = 10.2 Hz, 2H), 7.47
(d, J = 9.1 Hz, 1H), 7.33–7.30 (m, 3H), 7.18 (d, J = 9.6Hz,
1H), 7.12 (t, J = 9.1 Hz, 1H), 2.52 (s, 3H). This spectrum is
in agreement with previously reported spectral data.34
for CD2Cl2 and δH = 2.08 ppm for toluene-d8; δC
77.2 ppm for CDCl3, δC = 118.69 ppm for CD3CN, δC
=
=
53.84 ppm for CD2Cl2 or δ = 20.4 ppm for toluene-d8 in
13C NMR spectroscopy experiments).
The following abbreviations were used for signal mul-
tiplicities: app = apparent, s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, br = broad. 11B and 19F
NMR spectroscopy experiments are referenced to the
absolute frequency of 0 ppm in the H dimension accord-
ing to the Xi scale. NMR spectroscopy signal assignments
Methyl(2-(p-tolylethynyl)phenyl)sulfane (1b-ii). Me-
thyl(2-(p-tolylethynyl)phenyl)sulfane was synthesized
1
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using a literature procedure35 in 99% yield. 1H NMR
(CDCl3, 500 MHz): δ 7.48–7.46 m, 3H), 7.29 (td, J = 7.7, 1.4
Hz, 1H), 7.18–7.15 (m, 3H), 7.11 (td, J = 7.5, 1.2 Hz, 1H),
2.51 (s, 3H), 2.37 (s, 3H). This spectrum is in agreement
with previously reported spectral data.35
The organic layer was dried over Na2SO4, filtered, and
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2
3
4
5
6
7
8
concentrated in vacuo. The resulting oily residue was
purified by column chromatography using an elution
gradient of 0% to 5% EtOAc in hexanes. Product-
containing fractions were combined and concentrated in
vacuo, and volatiles were removed at c.a. 10 mTorr for 18
h to afford 1b-iv as a yellow solid (493 mg, 97% yield).
1H NMR (CDCl3, 600 MHz): δ 7.56 (ddd, J = 8.8, 5.4, 2.2 Hz,
2H), 7.47 (dd, J = 7.6, 1.3 Hz, 1H), 7.31 (td, J = 7.9, 1.4 Hz,
1H), 7.18 (d, J = 7.9 Hz, 1H), 7.11 (td, J = 7.6, 1.1 Hz, 1H),
7.05 (tt, J = 8.8, 2.1 Hz, 2H), 2.51 (s, 3H). 13C NMR (CDCl3,
151 MHz): δ 162.8 (d, J = 249.8 Hz), 141.8, 133.6 (d, J =
8.3 Hz), 132.3, 129.0, 124.3 (d, J = 28.3 Hz), 121.3, 119.4
(d, J = 3.5 Hz), 115.9, 115.7, 94.9, 86.7, 15.2. HRMS
(TOFMS-CI+) m/z Calcd for C15H11FS ([M]+): 242.0565;
Found 242.0557.
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Methyl 4-((2-(methylthio)phenyl)ethynyl)benzoate (1b-
iii). In an N2-filled glovebox, a 20 mL scintillation vial was
charged with methyl 4-iodobenzoate (580 mg, 2.2 mmol,
1.0 equiv), (PPh3)2PdCl2 (77 mg, 0.011 mmol, 0.050
equiv), CuI (42 mg, 0.22 mmol, 0.10 equiv), and a stir bar.
In a separate dram vial, SI-2 (420 mg, 2.9 mmol, 1.3
equiv) was dissolved in Et3N (6.1 mL). This solution was
then added to the substrate-containing vial via pipette,
and the mixture-containing vial was capped and removed
from the glovebox. The solution was stirred for 18 h at
ambient temperature. At this time, TLC indicated com-
plete consumption of starting material. The reaction
mixture was diluted with 100 mL EtOAc and washed with
saturated aqueous NH4Cl (1 × 20 mL), water (1 × 20 mL),
and brine (1 × 20 mL). The organic layer was dried over
Na2SO4, filtered, and concentrated in vacuo. The resulting
oily residue was purified by column chromatography
using an elution gradient of 0% to 15% EtOAc in hexanes.
Product-containing fractions were combined and concen-
trated in vacuo, and volatiles were removed at c.a. 10
mTorr for 18 h to afford 1b-iii as a yellow solid (470 mg,
Methyl(2-((4-
(trifluoromethyl)phenyl)ethynyl)phenyl)sulfane (1b-v). In
an N2-filled glovebox, a 20 mL scintillation vial was
charged with methyl 4-iodobenzotrifluoride (0.31 mL,
2.1 mmol, 1.0 equiv), (PPh3)2PdCl2 (77 mg, 0.011 mmol,
0.050 equiv), CuI (40. mg, 0.21 mmol, 0.10 equiv), and a
stir bar. In a separate dram vial, SI-2 (373 mg, 2.5 mmol,
1.2 equiv) was dissolved in Et3N (6.4 mL). This solution
was then added to the substrate-containing vial via pi-
pette, which was capped and removed from the glovebox.
The solution was stirred for 18 h at ambient tempera-
ture. At this time, TLC indicated complete consumption of
starting material. The reaction mixture was diluted with
100 mL EtOAc and washed with saturated aqueous NH4Cl
(1 × 20 mL), water (1 × 20 mL), and brine (1 × 20 mL).
The organic layer was dried over Na2SO4, filtered, and
concentrated in vacuo. The resulting oily residue was
purified by column chromatography using an elution
gradient of 0% to 5% EtOAc in hexanes. Product-
containing fractions were combined and concentrated in
vacuo, and volatiles were removed at c.a. 10 mTorr for 18
1
75% yield). H NMR (CDCl3, 600 MHz): δ 8.02 (dt, J = 8.4,
1.7 Hz, 2H), 7.63 (dt, J = 8.4, 1.7 Hz, 2H), 7.49 (dd, J = 7.6,
1.2 Hz, 1H), 7.33 (td, J = 8.0, 1.5 Hz, 1H), 7.19 (d, J = 7.8
Hz, 1H), 7.13 (td, J = 7.6, 1.1 Hz, 1H), 3.93 (s, 3H), 2.52 (s,
3H). 13C NMR (CDCl3, 151 MHz): δ 166.7, 142.2, 132.5,
131.6, 129.7, 129.6, 129.4, 128.0, 124.4, 124.3, 120.8,
95.1, 89.9, 52.4, 15.2. HRMS (TOFMS-CI+) m/z Calcd for
C17H14O2S ([M]+): 282.0714; Found 282.0714.
1
h to afford 1b-v as a yellow oil (540 mg, 88% yield). H
NMR (CDCl3, 600 MHz): δ 7.68 (d, J = 8.0 Hz, 2H), 7.61 (d,
J = 8.3 Hz, 2H), 7.50 (dd, J = 7.6, 1.3 Hz, 1H), 7.34 (td, J =
7.8, 1.4 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.13 (td, J = 7.5,
1.0 Hz, 1H), 2.53 (s, 3H). This spectrum is in agreement
with previously reported spectral data.36
(2-((4-Fluorophenyl)ethynyl)phenyl)(methyl)sulfane
(1b-iv). In an N2-filled glovebox, a 20 mL scintillation vial
was charged with methyl 4-fluoroiodobenzoate (0.24 mL,
2.1 mmol, 1.0 equiv), (PPh3)2PdCl2 (77 mg, 0.011 mmol,
0.050 equiv), CuI (40. mg, 0.21 mmol, 0.10 equiv), and a
stir bar. In a separate dram vial, SI-2 (373 mg, 2.5 mmol,
1.2 equiv) was dissolved in Et3N (6.4 mL). This solution
was then added to the substrate-containing vial via pi-
pette, which was capped and removed from the glovebox.
The solution was stirred for 18 h at ambient tempera-
ture. At this time, TLC indicated complete consumption of
starting material. The reaction mixture was diluted with
100 mL EtOAc and washed with saturated aqueous NH4Cl
(1 × 20 mL), water (1 × 20 mL), and brine (1 × 20 mL).
(2-((4-Bromophenyl)ethynyl)phenyl)(methyl)sulfane
(1b-vi).
(2-((4-
Bromophenyl)ethynyl)phenyl)(methyl)sulfane was syn-
1
thesized using a literature procedure34 in 86% yield. H
NMR (CDCl3, 600 MHz): δ 7.50–7.46 (m, 3H), 7.44–7.43
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(m, 2H), 7.32 (dd, J = 7.9, 1.3 Hz, 1H), 7.19 (d, J = 8.0 Hz, The ClBcat/d8-toluene containing solution was then
1
2
3
4
5
6
7
8
1H), 7.11 (t, J = 7.5 Hz, 1H), 2.51 (s, 3H). This spectrum is
transferred via pipette to the vial containing compound
1. The vial was capped and placed in a pre-heated alumi-
num block at 100 oC. The mixture was heated for 4 h. The
mixture was then cooled to room temperature before the
contents of this vial were then transferred to a J. Young
NMR tube and 0.3 mL of d8-toluene was added. The tube
was then sealed and removed from the glovebox. 1H NMR
spectroscopy was used to identify the resonances corre-
sponding to the desired thioboration products 6b (i–
viii).
in agreement with previously reported spectral data.34
9
(2-((4-methoxyphenyl)ethynyl)phenyl)(methyl)sulfane
(1b-vii). In an N2-filled glovebox, a 20 mL scintillation
vial was charged with 4-iodoanisole (740. mg, 3.2 mmol,
1.0 equiv), (PPh3)2PdCl2 (110 mg, 0.16 mmol, 0.050
equiv), CuI (61 mg, 0.32 mmol, 0.10 equiv), and a stir bar.
In a separate dram vial, SI-2 (570 mg, 3.8 mmol, 1.2
equiv) was dissolved in Et3N (9.6 mL). This solution was
then added to the substrate-containing vial via pipette,
which was capped and removed from the glovebox. The
solution was stirred for 18 h at ambient temperature. At
this time, TLC indicated complete consumption of start-
ing material. The reaction mixture was diluted with 100
mL Et2O and washed with saturated aqueous NH4Cl (1 ×
20 mL), water (1 × 20 mL), and brine (1 × 20 mL). The
organic layer was dried over Na2SO4, filtered, and con-
centrated in vacuo. The resulting oily residue was puri-
fied by column chromatography using an elution gradient
of 0% to 10% EtOAc in hexanes. Product-containing frac-
tions were combined and concentrated in vacuo, and
volatiles were removed at c.a. 10 mTorr for 18 h to afford
1b-vii as a yellow oil (540. Mg, 67% yield). 1H NMR
(CDCl3, 500 MHz): δ 7.54 (d, J = 8.8 Hz, 2H), 7.48 (d, J =
7.6 Hz, 1H), 7.29 (td, J = 7.9 Hz, 1.4 Hz, 1H), 7.17 (d, J = 7.9
Hz, 1H), 7.09 (td, J = 7.6, 1.0 Hz, 1H), 6.87 (d, J = 8.8 Hz,
2H), 3.82 (s, 3H), 2.51 (s, 3H). This spectrum is in agree-
ment with previously reported spectral data.35
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Procedure for Competition Experiments to Determine
the Hammett Plot. This procedure was performed in an
N2-filled glovebox.
A dram vial was charged with
B-chlorocatecholborane (13 mg, 0.087 mmol, 1.0 equiv)
and 0.4 mL of d8-toluene. A separate dram vial was
charged with mesitylene (6.0 ꢁL, 0.043 mmol, 0.50
equiv), 1b-A (0.26 mmol, 3.0 equiv) and 1b-B (0.26
mmol, 3.0 equiv). The ClBcat/d8-toluene containing solu-
tion was then transferred via pipette to the vial contain-
ing compounds 1b-A and 1b-B. The contents of this vial
were then transferred to a J. Young NMR tube, which was
capped, and removed from the glovebox. The tube was
o
then placed in a preheated oil bath at 100 C. Single-scan
1H spectra were taken at time points t = 0 h (before heat-
ing), and at t = 2 h and 4 h, for which the tube was briefly
removed from the heating bath. The resonances corre-
sponding to 6b-A and 6b-B were compared to the inter-
nal standard to determine the relative reaction rates (k)
for each competition experiment. The product ratios did
not change upon standing.
Methyl(2-(m-tolylethynyl)phenyl)sulfane (1b-ix). In an
N2-filled glovebox, a 20 mL scintillation vial was charged
with 3-iodotoluene (0.27 mL, 2.1 mmol, 1.0 equiv),
(PPh3)2PdCl2 (73 mg, 0.010 mmol, 0.050 equiv), CuI (39
mg, 0.20 mmol, 0.10 equiv), and a stir bar. In a separate
dram vial, SI-2 (365 mg, 2.50 mmol, 1.2 equiv) was dis-
solved in Et3N (12 mL). This solution was then added to
the substrate-containing vial via pipette, which was
capped and removed from the glovebox. The solution
was stirred for 18 h at ambient temperature. At this time,
TLC indicated complete consumption of starting material.
The reaction mixture was diluted with 100 mL Et2O and
washed with saturated aqueous NH4Cl (1 × 20 mL), water
(1 × 20 mL), and brine (1 × 20 mL). The organic layer was
dried over Na2SO4, filtered, and concentrated in vacuo.
The resulting oily residue was purified by column chro-
matography using an elution gradient of 0% to 5% EtOAc
in hexanes. Product-containing fractions were combined
and concentrated in vacuo, and volatiles were removed
at c.a. 10 mTorr for 18 h to afford 1b-ix as a yellow oil
N,N-Dimethyl-4-((2-
(methylthio)phenyl)ethynyl)aniline
(1b-viii).
N,N-
Dimethyl-4-((2-(methylthio)phenyl)ethynyl)aniline was
synthesized using a literature procedure34 in 97% yield.
1H NMR (CDCl3, 600 MHz): δ 7.47 (d, J = 10.9 Hz, 3H),
7.26 (t, J = 9.5 Hz, 1H), 7.16 (d, J = 9.3 Hz, 1H), 7.10 (t, J =
9.0 Hz, 1H), 6.66 (d, J = 10.7 Hz, 2H), 2.99 (s, 6H), 6.51 (s,
3H). This spectrum is in agreement with previously re-
ported spectral data.34
Procedure for Reference Cyclizations of Thionasioles 1b
(i–viii). In order to monitor the competition reactions by
1H NMR spectroscopy, it was necessary to run the indi-
vidual substrates 1b(i–viii) under thioboration condi-
tions to determine product resonances. This procedure
was performed in an N2-filled glovebox. A dram vial was
charged with B-chlorocatecholborane (42 mg, 0.27 mmol,
1.4 equiv) and 0.15 mL of d8-toluene. A separate dram
vial was charged with 1b(i–viii) (0.20 mmol, 1.0 equiv).
1
(475 mg, 95% yield). H NMR (CDCl3, 600 MHz): δ 7.48
(dd, J = 7.6, 1.4 Hz, 1H), 7.41–7.38 (m, 2H), 7.30 (td, J =
7.9, 1.5 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.19 (d, J = 7.7 Hz,
1H), 7.16 (d, J = 7.6 Hz, 1H), 7.11 (td, J = 7.5, 1.1 Hz, 1H),
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2.52 (s, 3H), 2.36 (s, 3H). 13C NMR (CDCl3, 151 MHz): δ
141.8, 138.1, 132.4, 132.3, 129.5, 128.83, 128.82, 128.4,
124.4, 124.2, 123.1, 121.6, 96.2, 86.7, 21.4, 15.2. HRMS
(TOFMS-CI+) m/z Calcd for C16H14S ([M]+): 238.0816;
Found 238.0821.
residue was purified by column chromatography using
1
2
3
4
5
6
7
8
an elution gradient of 0% to 3% EtOAc in hexanes. Prod-
uct-containing fractions were combined and concentrat-
ed in vacuo, and volatiles were removed at c.a. 10 mTorr
for 18 h to afford 1b-xi as a yellow oil (390 mg, 94%
yield). 1H NMR (CDCl3, 600 MHz): δ 7.57–7.56 (m, 1H),
7.48 (dd, J = 7.6, 1.3 Hz, 1H), 7.45 (dt, J = 7.4, 1.4 Hz, 1H),
7.34–7.27 (m, 3H), 7.19 (d, J = 7.8 Hz, 1H), 7.12 (td, J =
7.5, 1.1 Hz, 1H), 2.52 (s, 3H). 13C NMR (CDCl3, 151 MHz): δ
142.1, 134.3, 132.5, 131.5, 129.8, 129.7, 129.3, 128.8,
125.1, 124.4, 124.3, 120.9, 94.4, 88.2, 15.1. HRMS
(TOFMS-CI+) m/z Calcd for C15H11SClNH4 ([M+NH4]+):
276.0614; Found 276.0602.
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Methyl(2-(o-tolylethynyl)phenyl)sulfane (1b-x). In an N-
2-filled glovebox, a 20 mL scintillation vial was charged 2-
iodoanisole (0.49 mL, 3.5 mmol, 1.0 equiv), (PPh3)2PdCl2
(120. mg, 0.180 mmol, 0.050 equiv), CuI (67 mg, 0.35
mmol, 0.10 equiv), and a stir bar. In a separate dram vial,
2-ethynyltoluene (0.57 mL, 4.6 mmol, 1.3 equiv) was
diluted in Et3N (11 mL). This solution was then added to
the substrate-containing vial via pipette, which was
capped and removed from the glovebox. The solution
was stirred for 18 h at ambient temperature. At this time,
TLC indicated complete consumption of starting material.
The reaction mixture was diluted with 100 mL Et2O and
washed with saturated aqueous NH4Cl (1 × 20 mL), water
(1 × 20 mL), and brine (1 × 20 mL). The organic layer was
dried over Na2SO4, filtered, and concentrated in vacuo.
The resulting oily residue was purified by column chro-
matography using an elution gradient of 0% to 5% EtOAc
in hexanes. Product-containing fractions were combined
and concentrated in vacuo, and volatiles were removed
at c.a. 10 mTorr for 18 h to afford 1b-x as a yellow liquid
(420. mg, 50% yield). 1H NMR (CDCl3, 600 MHz):
δ 7.55 (d, J = 7.4 Hz, 1H), 7.51 (dd, J = 7.6, 1.4 Hz, 1H), 7.31
(td, J = 7.7, 1.4 Hz, 1H), 7.24 (dd, J = 4.8, 1.0 Hz, 2H), 7.19–
7.16 (m, 2H), 7.12 (td, J = 7.5, 1.1 Hz, 1H), 2.58 (s, 3H),
2.52 (s, 3H). 13C NMR (CDCl3, 151 MHz): δ 141.6, 140.5,
132.5, 132.2, 129.6, 128.8, 128.6, 125.7, 124.4, 124.2,
123.1, 121.7, 95.0, 90.8, 21.2, 15.2. HRMS (TOFMS-CI+)
m/z Calcd for C16H14S ([M]+): 238.0816; Found 238.0815.
(2-((2-Chlorophenyl)ethynyl)phenyl)(methyl)sulfane
(1b-xii). In an N2-filled glovebox, a 20 mL scintillation vial
was charged with 2-chloro-iodobenzene (0.16 mL, 1.3
mmol, 1.0 equiv), (PPh3)2PdCl2 (46 mg, 0.065 mmol,
0.050 equiv), CuI (25 mg, 0.13 mmol, 0.10 equiv), and a
stir bar. In a separate dram vial, SI-2 (250 mg, 1.70 mmol,
1.3 equiv) was dissolved in Et3N (3.9 mL). This solution
was then added to the substrate-containing vial via pi-
pette, which was capped and removed from the glovebox.
The solution was stirred for 18 h at ambient tempera-
ture. At this time, TLC indicated complete consumption of
starting material. The reaction mixture was diluted with
100 mL Et2O and washed with saturated aqueous NH4Cl
(1 × 20 mL), water (1 × 20 mL), and brine (1 × 20 mL).
The organic layer was dried over Na2SO4, filtered, and
concentrated in vacuo. The resulting oily residue was
purified by column chromatography using an elution
gradient of 0% to 3% EtOAc in hexanes. Product-
containing fractions were combined and concentrated in
vacuo, and volatiles were removed at c.a. 10 mTorr for 18
1
h to afford 1b-xii as a yellow oil (329 mg, 98% yield). H
NMR (CDCl3, 600 MHz): δ 7.62–7.61 (m, 1H), 7.54 (dd, J =
7.7, 1.3 Hz, 1H), 7.44–7.43 (m, 1H), 7.33 (td, J = 7.9, 1.4
Hz, 1H), 7.28–7.23 (m, 2H), 7.20 (d, J = 7.7 Hz, 1H), 7.13
(td, J = 7.5, 1.1 Hz, 1H), 2.53 (s, 3H). 13C NMR (CDCl3, 151
MHz): δ 142.0, 136.0, 133.6, 132.8, 129.5, 129.5, 129.3,
126.6, 124.4, 124.4, 123.3, 121.2, 92.6, 92.0, 15.3. HRMS
(TOFMS-CI+) m/z Calcd for C15H11SCl ([M]+): 258.0270;
Found 258.0262.
(2-((3-Chlorophenyl)ethynyl)phenyl)(methyl)sulfane
(1b-xi). In an N2-filled glovebox, a 20 mL scintillation vial
was charged with 3-chloro-iodobenzene (0.15 mL, 1.2
mmol, 1.0 equiv), (PPh3)2PdCl2 (42 mg, 0.060 mmol,
0.050 equiv), CuI (23 mg, 0.12 mmol, 0.10 equiv), and a
stir bar. In a separate dram vial, SI-2 (231. mg, 1.60
mmol, 1.3 equiv) was dissolved in Et3N (3.6 mL). This
solution was then added to the substrate-containing vial
via pipette, which was capped and removed from the
glovebox. The solution was stirred for 18 h at ambient
temperatures. At this time, TLC indicated complete con-
sumption of starting material. The reaction mixture was
diluted with 100 mL Et2O and washed with saturated
aqueous NH4Cl (1 × 20 mL), water (1 × 20 mL), and brine
(1 × 20 mL). The organic layer was dried over Na2SO4,
filtered, and concentrated in vacuo. The resulting oily
Procedure for Cyclizations of Thionasioles 1b-i, 1b-ii
and 1b(ix–xii). This procedure was performed in an N2-
filled glovebox.
A dram vial was charged with
B-chlorocatecholborane (99 mg, 0.64 mmol, 1.4 equiv)
and 0.35 mL of d8-toluene. A separate dram vial was
charged with 1b(ix–xii) (0.46 mmol, 1.0 equiv) and me-
sitylene (20. ꢁL, 0.14 mmol, 0.33 equiv). The ClBcat/d8-
toluene containing solution was then transferred via
pipette to the vial containing compound 1b(ix–xii). The
contents of the vial were then transferred to a J. Young
NMR tube. The tube was then capped, removed from the
glovebox, and placed into a preheated 100 oC oil bath.
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1
Single-scan H spectra were taken at time points t = 0 h
(before heating), and t = 2 h, for which the tube was
briefly removed from the heating bath. The resonances
corresponding to thioboration products 6b(ix–xii) were
7.6 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 3.93 (s, 3H), 3.40 (s,
1H). This spectrum is in agreement with previously re-
ported spectral data.38
1
2
3
4
5
6
1
Methyl 2-((2-(methylthio)phenyl)ethynyl)benzoate (1b-
xiii). Methyl 2-((2-(methylthio)phenyl)ethynyl)benzoate
was synthesized using a literature procedure according
compared to the internal standard to determine H NMR
spectroscopy yields. Each experiment was replicated. The
yield and error are reported as the average and standard
deviation of two runs, respectively.
1
to a literature procedure38 in 79% yield. H NMR (CDCl3,
7
8
9
600 MHz): δ 7.94 (dd, J = 7.9, 1.4 Hz, 1H), 7.73 (dd, J = 7.6,
1.1 Hz, 1H), 7.54 (dd, J = 7.6, 1.2 Hz, 1H), 7.49 (dt, J = 7.5,
1.4 Hz, 1H), 7.39 (dt, J = 7.7, 1.3 Hz, 1H), 7.31 (dt, J = 7.9,
1.4 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 7.13 (dt, J = 7.5,
0.9 Hz, 1H), 3.93 (s, 3H), 3.39 (s, 3H). This spectrum is in
agreement with previously reported spectral data.38
(2-(Hex-1-yn-1-yl)phenyl)(methyl)sulfane (1a). (2-(Hex-
1-yn-1-yl)phenyl)(methyl)sulfane was synthesized using
a literature procedure34 in 92% yield. 1H NMR (CDCl3,
600 MHz): δ 7.36 (d, J = 7.6 Hz, 1H), 7.24 (t, J = 7.9 Hz,
1H), 7.12 (d, J = 7.5 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 2.50
(t, J = 7.0 Hz, 2H), 2.47 (s, 3H), 1.64 (quin, J = 7.9 Hz, 2H),
1.60–1.50 (m, 2H), 1.25 (t, J = 7.4 Hz, 3H). This spectrum
is in agreement with previously reported spectral data.34
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Procedure for Competitive Cyclization of Thioanisole 1a
and Thioether 7. This procedure was performed in an N2-
filled glovebox.
A dram vial was charged with
B-chlorocatecholborane (13 mg, 0.087 mmol, 1.0 equiv)
and 0.2 mL of d8-toluene. Another dram vial was charged
with 1a (0.26 mmol, 3.0 equiv) and 0.1 mL of d8-toluene.
A third dram vial was charged with 7 (0.26 mmol, 3.0
equiv) and 0.1 mL of d8-toluene. The 1a/d8-toluene con-
taining solution was then transferred via pipette to the
vial containing 7/d8-toluene, which was then transferred
via pipette to the vial containing ClBcat/d8-toluene. The
final solution was then charged with mesitylene (6.0 ꢁL,
0.043 mmol, 0.50 equiv) and then transferred to a J.
Young NMR tube, sealed and removed from the glovebox.
The tube was then placed in a preheated oil bath at 100
Hept-3-yn-1-yl 4-methylbenzenesulfonate (SI-4). Hept-
3-yn-1-yl 4-methylbenzenesulfonate was synthesized
using a literature procedure37 in 58% yield. 1H NMR
(CDCl3, 600 MHz): δ 7.80 (d, J = 7.8 Hz, 2H), 7.34 (d, J =
7.7 Hz, 2H), 4.06 (q, J = 7.3 Hz, 2H), 2.51 (d, J = 7.1 Hz,
2H), 2.45 (s, 3H), 2.5 (d, J = 7.9 Hz, 2H), 1.44 (quin, J =
7.2 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H). This spectrum is in
agreement with previously reported spectral data.37
1
oC. Single-scan H spectra were taken at time points t = 0
Hept-3-yn-1-yl(methyl)sulfane
(7).
Hept-3-yn-1-
h (before heating), and t = 2 h and 4 h, for which the tube
was briefly removed from the heating bath. The reso-
nances corresponding to 6a and 8 were compared to the
internal standard to determine the relative yields of 6a
and 8.
yl(methyl)sulfane was synthesized using a literature
1
procedure34 in 14% yield. H NMR (CDCl3, 600 MHz): δ
2.63 (t, J = 8.0 Hz, 2H), 2.47–2.44 (m, 2H), 2.14–2.11 (m,
5H), 1.50 (sext., J = 7.3 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H).
This spectrum is in agreement with previously reported
spectral data.34
Procedure for Intramolecular Competitive Cyclization of
6b-xiii and 9. This procedure was performed in an N2-
filled glovebox.
A dram vial was charged with
B-chlorocatecholborane (141 mg, 0.91 mmol, 1.4 equiv)
and 0.4 mL of d8-toluene. A separate dram vial was
charged with 1b-xiii (0.65 mmol, 1.0 equiv). The
ClBcat/d8-toluene containing solution was then trans-
ferred via pipette to the vial containing compounds 1b-
xiii, and the solution was charged with mesitylene (30
ꢁL, 0.217 mmol, 0.30 equiv). The contents of this vial
were then transferred to a J. Young NMR tube. The vial
was rinsed once with 0.1 mL of d8-toluene and it was
added to the J. Young NMR tube. The tube was then
sealed and removed from the glovebox. The tube was
Methyl 2-((trimethylsilyl)ethynyl)benzoate (SI-6). Me-
thyl 2-((trimethylsilyl)ethynyl)benzoate was synthesized
using a literature procedure38 in 79% yield. 1H NMR
(CDCl3, 600 MHz): δ 7.90 (app d, J = 7.6 Hz, 1H), 7.58
(app d, J = 7.5 Hz, 1H), 7.44 (td, J = 7.6, 0.8 Hz, 1H), 7.36
(app t, J = 7.6 Hz, 1H), 3.92 (s, 3H), 0.27 (s, 9H). This spec-
trum is in agreement with previously reported spectral
data.38
o
1
placed in a preheated oil bath at 100 C. Single-scan H
spectra were taken at time points t = 0 h, 2 h, and 4 h for
which the tube was briefly removed from the heating
bath. The resonances corresponding to 6b-xiii and 9
were compared to the internal standard to determine the
relative product ratios for the competition experiment.
Preparation of Substrates 1a and 6a for 13C KIE Meas-
urements. This procedure was performed in an N2-filled
glovebox. A 20 mL scintillation vial was charged sequen-
tially with compound 1a (2.75 g, 12.3 mmol, 1.00 equiv),
Methyl
2-ethynylbenzoate
(SI-7).
Methyl
2-
ethynylbenzoate was synthesized using a literature pro-
1
cedure38 in 83% yield. H NMR (CDCl3, 600 MHz): δ 7.94
(d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.47 (t, J =
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toluene (11.5 mL), B-chlorocatecholborane (2.65 g, 17.2
167.9 (m, 6F, m-F, minor + major rotamers). 13C NMR
1
2
3
4
5
6
7
8
mmol, 1.40 equiv), and a stir bar. The vial was then
sealed and placed in a preheated aluminum block at 85 oC
and stirred. The mixture was vented by removing the cap
briefly every 20 minutes to prevent pressure build up
from the CH3Cl byproduct. After 134 min, a small aliquot
(~10 ꢁL) of the reaction mixture was removed, diluted in
d8-toluene, and analyzed by single scan 1H NMR to de-
termine reaction conversion (75% conversion was de-
tected at t = 134 min). In order to recover unreacted
(101 MHz, CD2Cl2): δ 133.5, 133.5, 128.7, 128.6, 127.6,
126.2, 126.1, 118.3, 33.8, 33.5, 11.3, 11.2, 10.6, 10.5, 10.0,
9.9, 9.3. (Only partial assignment, full attribution not
attempted because of low resolution and low solubility.)
11B NMR (128 MHz, CD2Cl2) δ -15.1. HRMS (FAB–) m/z
Calcd. for C30H11BF15S– ([M-H]-): 699.0440; Found
~
699.0450. IR (ATR)
ν
(cm–1): 3027, 1642, 1515, 1457,
1445, 1272, 1091, 1083, 970, 968, 775, 691. UV-Vis
= 2.52 × 104 L mol–1 cm–
9
(CH2Cl2, 20 °C): max = 231 nm (
λ
ε
starting material for isotopic analysis,
a flask was
1), 268 nm ( = 5.43 × 103 L mol–1 cm–1) and 320 nm (
ε ε =
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
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39
40
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43
44
45
46
47
48
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50
51
52
53
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55
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57
58
59
60
charged with MeOH (10 mL) and Et3N (10 mL), and then
3.22 × 103 L mol–1 cm–1). Mp: 192–194 °C.
o
cooled to 0 C. The reaction mixture-containing vial was
removed from the glovebox and added to this flask. The
Tetramethylammonium
o
mixture was then stirred for 15 min at 0 C. The mixture
(2-cyclopropylbenzo[b]thiophen-3-yl)tris(pentafluoro)phe
nylborate (20). The 2-alkynyl thioanisole substrate 1d
(100. mg, 0.531 mmol, 1.0 equiv.) was dissolved in 5 mL
of CH2Cl2, and a solution of B(C6F5)3 (273 mg, 0.533
mmol, 1.00 equiv) in 5 mL of CH2Cl2 was added with a
was then transferred to a separatory funnel, diluted with
Et2O (150 mL), washed with water (3 × 30 mL), and brine
(1 × 30 mL). The organic layer was dried over Na2SO4,
filtered, and concentrated in vacuo. The resulting oily
residue was purified by column chromatography using
an elution gradient of 0% to 5% EtOAc in hexanes. Start-
ing material (1a)-containing fractions were combined
and concentrated in vacuo, and volatiles were removed
at c.a. 10 mTorr for 18 h to recover 617 mg of starting
material 1a. Spectral data were identical to those previ-
ously obtained for this compound. This experiment was
repeated on the 2.75 g scale, stopped at 74% conversion,
and 664 mg was recovered of 1a.
syringe. After stirring for 1 hour at 20 oC in CH2Cl2
a
white suspension was formed and a white solid precipi-
tated (compound 19). Compound 19 was treated by
adding tetramethylammonium chloride Me4N+Cl– as a
solid (60. mg, 0.55 mmol, 1.0 equiv.) and 5 mL of CH3CN
were added to the suspension (low solubility of Me4N+Cl–
in CH2Cl2). After vigorous stirring overnight, approxi-
mately half of the solvent was removed under vacuum
and 20 mL of Et2O were added to the Schlenk flask, which
resulted in the immediate precipitation of a white solid.
Filtration under nitrogen and washing the solid twice
with 15 mL of Et2O and drying under high vacuum
(10-3 mbar) for 10 h gave the benzothiophene 20 Me4N+
(2-cyclopropyl-1-methyl-1H-benzo[b]thiophenium-3-
yl)tris(pentafluoro)phenylborate (19). In a flame-dried
Schlenk flask under Ar, the 2-alkynyl thioanisole sub-
strate 1d (55 mg, 0.29 mmol, 1.0 equiv.) was dissolved in
2 mL of CH2Cl2, and a solution of B(C6F5)3 (150. mg,
0.293 mmol, 1.01 equiv) in 2 mL of CH2Cl2 was added
dropwise. After stirring 1 hour at 20 oC in CH2Cl2, the
clear solution became a white suspension, and 10 mL of
n-pentane was added to ensure full precipitation of a
white solid. After filtration under nitrogen and washing
the solid twice with 10 mL of a n-pentane:CH2Cl2 (8:2)
mixture, and drying under high vacuum (10-3 mbar) for 6
h, the 1-methyl-1-benzothiophenium borate intermediate
1
in 78% yield (316 mg, 0.416 mmol). H NMR (400 MHz,
3
CD3CN): δ 7.60 – 7.63 (m, 1H, H-4), 7.52 (app. d, JH-H
=
8.0 Hz, 1H, H-7), 6.95-7.03 (m, 2H, H-5 and H-6), 3.07
2
(app. t, JN-H = 0.6 Hz, 12H, Me4N+), 1.94 – 1.99 (m, 1H, H-
10, signal overlapped with CD3CN residual solvent peak),
0.74 – 0.81 (m, 1H, H-11 or H-12), 0.64 – 0.72 (m, 3H, H-
11 and H-12). 1H NMR (400 MHz, DMSO-d6): δ 7.60 (d, 3JH-
H = 7.4 Hz, 1H, H-4), 7.40 (d, 3JH-H = 7.6 Hz, 1H, H-7), 6.93 –
7.00 (m, 2H, H-5 and H-6), 3.09 (br. s, 12H, Me4N+), 1.83
(p, 3JH-H = 6.4 Hz, 1H, H-10), 0.85 – 0.73 (m, 1H, H-11 or H-
12), 0.69 – 0.46 (m, 3H, H-11 and H-12). 19F NMR (376
1
19 was isolated in 81% yield (165 mg, 0.236 mmol). H
NMR (400 MHz, CD2Cl2): δ 7.83 (app. d, J = 8.1 Hz, 1H,
major rotamer), 7.72 (app. t, J = 8.0 Hz, 3H, minor + major
rotamer), 7.50–7.57 (m, 2H, minor + major rotamer),
7.43 (app. t, J = 7.6 Hz, 2H, minor + major rotamer), 3.10
(s, 3H, S+Me of minor rotamer), 2.91 (s, 3H, S+Me of major
rotamer), 1.98 (p, J = 7.9 Hz, 1H, cyclopropyl-CH of minor
rotamer), 1.75 (p, J = 8.1 Hz, 1H, cyclopropyl-CH of major
rotamer), 1.37–0.58 (m, 8H, cyclopropyl-CH2 of minor
and major rotamers). 19F NMR (376 MHz, CD2Cl2): δ -
127.2 (bs, 1F, o-F, major rotamer), -129.1 – -129.4 (m, 1F,
3
MHz, CD3CN): δ -127.80 (app. t, JF-F = 27.6 Hz, 1F, o-
3
F), -129.23 – -129.40 (m, 1F, o-F), -130.29 (app. d, JF-F
=
24.2 Hz, 1F, o-F), -131.19 (br. s, 1F, o-F), -132.55 (app. d,
3JF-F = 24.5 Hz, 1F, o-F), -134.58 (br. s, 1F, o-F), -164.36 (t,
3
3JF-F = 19.7 Hz, 2F, 2 × p-F), -165.04 (t, JF-F = 19.8 Hz, 1F,
p-F), -168.00 – -168.38 (m, 3F, m-F), -168.46 – -169.07
(m, 3F, m-F). 13C NMR (101 MHz, CD3CN): δ 151.1 (m,
C6F5), 149.9 (m, C6F5), 149.0 (s, C9), 148.4 (m, C6F5),
147.5 (m, C6F5), 146.3 (s, C2), 143.4 (m, C6F5), 142.8 (m,
C6F5), 142.2 (m, C6F5), 141.6 (m, C6F5), 140.4 (m, C6F5),
139.6 (m, C6F5), 138.5 (m, C6F5), 138.2 (m, C6F5), 137.8 (s,
C8), 137.2 (m, C6F5), 136.1 (m, C6F5), 127.2 (br. s,
C3),124.5 (d, J = 9.0 Hz, C4), 123.2 (s, C5 or C6), 122.3 (s,
C5 or C6), 122.0 (s, C7), 56.1 (s, Me4N+), 14.0 (d, J = 9.9
Hz, C10), 12.1 (C11 or C12), 10.9 (C11 or C12). Attribu-
tion for quaternary carbons of C6F5 rings not attempted.
11B NMR (128 MHz, CD3CN): δ –14.8. HRMS (ESI–) m/z
Calcd. for C29H9BF15S– ([M-H]-): 685.02840; Found
3
o-F, minor + major rotamers), -129.6 (app. t., JF-F = 26.1
Hz, 1F, o-F, minor rotamer), -129.9 – -130.1 (m, 1F, o-F,
minor + major rotamers), -131.0 (bs, 1F, o-F, major rota-
mer), -131.6 (bs, 1F, o-F, minor rotamer), -132.5 – -132.6
(m, 1F, o-F, minor rotamer), -133.8 – -133.9 (m, 1F, o-F,
major rotamer), -134.9 (bs, 1F, o-F, minor rotamer), -
136.4 (bs, 1F, o-F, major rotamer), -162.2 – -162.4 (m, 2F,
3
2 × p-F, minor + major rotamers), -162.6 (app. t, JF-F
=
19.9 Hz, 1F, p-F, minor + major rotamers), -166.7 – -
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The Journal of Organic Chemistry
~
The Supporting Information is available free of charge on
the ACS Publications website.
685.02935. IR (ATR)
1448, 1266, 1073, 974, 961, 948, 767, 685. UV-Vis
(CH2Cl2, 20 °C): max = 237 nm (
= 2.64 × 104 L mol–1 cm–
1), 283 nm ( = 8.86 × 103 L mol–1 cm–1). Mp: 313–314 °C.
ν
(cm–1): 3010, 1644, 1511, 1455,
1
2
3
4
λ
ε
Plots of kinetic data analysis, UV-Vis, IR, 1H NMR and 13C
NMR spectra and crystal structure for compound characteri-
zation and details of computational analyses (PDF)
ε
5
Methyl(tris)(o-tolyl)phosphonium
6
7
8
9
(2-cyclopropylbenzo[b]thiophen-3-yl)tris(pentafluoro)phe
nylborate (20). The 2-alkynyl thioanisole substrate 1d
(100. mg, 0.531 mmol, 1.0 equiv.) was dissolved in 5 mL
of CH2Cl2, and a solution of B(C6F5)3 (273 mg, 0.533
mmol, 1.00 equiv) in 5 mL of CH2Cl2 was added with a
AUTHOR INFORMATION
Corresponding Author
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blums@uci.edu
singleton@chem.tamu.edu
guillaume.berionni@cup.lmu.de
syringe. After stirring for 1 hour at 20 oC in CH2Cl2
a
white suspension is formed and a white solid precipitat-
ed. Tri(o-tolyl)phosphine was added as a solid (162 mg,
0.532 mmol, 1.00 equiv.) the solution was stirred over-
night. Approximately half of the solvent was remove
under vacuum and 20 mL of n-pentane were introduced,
which resulted in the precipitation of a pale-brown solid.
Filtration under nitrogen, washing the solid three times
with 10 mL of n-pentane, and drying under high vacuum
(10–3 mbar) for 48 h, gave 20, MeP+(o-tolyl)3 in 53% yield
(281 mg, 0.280 mmol). Despite extensive drying under
high vacuum, traces of n-pentane remained in the final
product. 1H NMR (600 MHz, CD2Cl2): δ 7.75 – 7.71 (m, 3H,
17-H), 7.58 – 7.48 (m, 5H, 18-H and 4-H and 7-H), 7.40
(app. t, J = 7.3 Hz, 3H, 16-H), 7.14 (app. dd, J = 15.7,
7.9 Hz, 3H, 15-H), 6.99 – 6.91 (m, 2H, 5-H and 6-H), 2.67
(d, 1JP-H = 12.8 Hz, 3H, 13-H), 2.28 (d, 3JP-H = 1.4 Hz, 9H, 20-
H), 1.99 – 1.87 (m, 1H, 10-H), 0.79 – 0.57 (m, 4H, 11-H
and 12-H, signal overlapped with traces of n-pentane, see
description above). 19F NMR (376 MHz, CD2Cl2): δ -
Notes
The authors declare the following competing financial inter-
ests: U.S. patent 9,238,661 and provisional patent applica-
tion no. 61/906,040 have been filed by the University of
California.
Author Contributions
The manuscript was written through contributions of all
authors. / All authors have given approval to the final ver-
sion of the manuscript. / #These authors contributed equal-
ly.
ACKNOWLEDGMENT
This work was supported by
a grant from the NIH
(1R01GM098512-01), by the Alexander von Humboldt
Foundation through a fellowship to S.A.B., and by the Uni-
versity of California, Irvine. We thank Dr. Phillip R. Dennison
for NMR spectroscopy assistance. G.B. thanks Prof. Dr. Her-
bert Mayr and Dr. Armin R. Ofial for helpful discussions and
for invaluable support via the Deutsche Forschungsgemein-
schaft (SFB 749, project B1). J.O.B. and D.A.S. thank the NIH
(GM 45617) for their financial support.
3
127.01 (t, JF-F =27.7 Hz, 1F, o-F), -128.54 – -128.88 (m,
1F, o-F), -130.08 (d, 3JF-F = 24.0 Hz, 1F, o-F), -130.48 (t, 3JF-
F = 22.2 Hz, 1F, o-F), -132.28 (dt, 3JF-F = 25.4, 7.5 Hz, 1F, o-
3
F), -133.63 – -133.88 (m, 1F, o-F), -136.18 (br. d, JF-F
=
3
20.5 Hz, 1F, o-F), -164.03 (app. q., JF-F = 17.2 Hz, 2 F, 2 ×
p-F), -164.82 (t, JF-F = 20.6 Hz, 1F, p-F). -167.1 (dddd, J =
3
REFERENCES
24.6, 20.3, 8.4, 4.2 Hz, 1F, m-F), -167.27 (dddd, J = 24.9,
20.5, 8.2, 4.4 Hz, 1F, m-F), -167.44 (dddd, J = 25.1 Hz,
20.7, 7.9, 4.4 Hz, 1F, m-F), -167.68 (dddd, J = 25.0, 20.7,
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C
NMR (151 MHz, CD2Cl2): δ 150.2 (m, C6F5), 149.8 (m,
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Hz, C-15), 134.4 (d, J = 11.0 Hz, C-18), 128.4 (d, J = 13.2
Hz, C-16) 124.2 (d, J = 5.9 Hz, C-4), 122.5 (s, C-5 or C-6),
121.4 (s, C-5 or C-6), 121.3 (s, C-7), 117.3 (d, J = 85.1 Hz,
C-14), 22.9 (s) 14.55 (d, J = 57.3 Hz, C-20), 13.6 (d, J = 9.6
Hz, C-10), 11.8 (C11 or C12), 10.6 (C11 or C12). Full at-
tribution for quaternary carbons of C6F5 rings not at-
tempted. Contains traces of n-pentane at 14.2, 22.8 and
34.6 ppm, see description above). 31P NMR (162 MHz,
CD2Cl2): δ –14.8. 11B NMR (128 MHz, CD2Cl2): δ 21.6. IR
~
(ATR)
ν
(cm–1): 2927, 1640, 1510, 1455, 1269, 1079,
975, 747. Mp: 144–148 °C.
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