Scope and Mechanism of Iridium Porphyrin-Catalyzed S-H Insertion Reactions between Thiols and Diazo Esters

Article abstract of DOI:10.1021/acs.organomet.6b00947

The insertion of carbenes derived from ethyl diazoacetate (EDA), methyl diazoacetate (MDA), methyl phenyldiazoacetate (MPDA), and methyl (p-tolyl)diazoacetate (MTDA) into the S-H bonds of aromatic and aliphatic thiols was catalyzed by (5,10,15,20-tetratolylporphyrinato)methyliridium(III), Ir(TTP)CH₃, at ambient temperatures. Yields of the resulting thioether products were as high as 97% for aromatic thiols, with catalyst loadings as low as 0.07 mol %. Thiol binding to Ir(TTP)CH₃ was measured at 23 °C by titration studies, providing equilibrium constants, K_b, ranging from 4.25 × 10² to 1.69 × 10³ and increasing in the order p-nitrobenzenethiol < p-chlorobenzenethiol < benzenethiol < p-methylbenzenethiol < p-methoxybenzenethiol < benzyl mercaptan. Hammett plots were generated from the relative rates of S-H insertion, using different para-substituted benzenethiols in substrate competition experiments. In the presence of MDA and MTDA, the Hammett plots had slopes of ?0.12 ± 0.01 and ?0.78 ± 0.11, respectively. The Hammett data and kinetic studies are consistent with a mechanism that involves a rate-limiting nucleophilic attack of thiols on an iridium-carbene species, where the major species present in the reaction solution is an inactive, hexacoordinate Ir-thiol complex.

Full text of DOI:10.1021/acs.organomet.6b00947

Article
pubs.acs.org/Organometallics
Scope and Mechanism of Iridium Porphyrin-Catalyzed S−H Insertion
Reactions between Thiols and Diazo Esters
Taiwo O. Dairo and L. Keith Woo*
Department of Chemistry, Iowa State University, 1605 Gilman Hall, 2415 Osborn Drive, Ames, Iowa 50011-1021, United States
S
* Supporting Information
ABSTRACT: The insertion of carbenes derived from ethyl diazoacetate (EDA), methyl
diazoacetate (MDA), methyl phenyldiazoacetate (MPDA), and methyl (p-tolyl)-
diazoacetate (MTDA) into the S−H bonds of aromatic and aliphatic thiols was
catalyzed by (5,10,15,20-tetratolylporphyrinato)methyliridium(III), Ir(TTP)CH3, at
ambient temperatures. Yields of the resulting thioether products were as high as 97%
for aromatic thiols, with catalyst loadings as low as 0.07 mol %. Thiol binding to
Ir(TTP)CH3 was measured at 23 °C by titration studies, providing equilibrium
constants, Kb, ranging from 4.25 × 102 to 1.69 × 103 and increasing in the order p-
nitrobenzenethiol < p-chlorobenzenethiol < benzenethiol < p-methylbenzenethiol < p-
methoxybenzenethiol < benzyl mercaptan. Hammett plots were generated from the
relative rates of S−H insertion, using different para-substituted benzenethiols in
substrate competition experiments. In the presence of MDA and MTDA, the Hammett
plots had slopes of −0.12 0.01 and −0.78 0.11, respectively. The Hammett data and
kinetic studies are consistent with a mechanism that involves a rate-limiting nucleophilic
attack of thiols on an iridium-carbene species, where the major species present in the
reaction solution is an inactive, hexacoordinate Ir-thiol complex.
tetratolylporphyrinatomethyliridium(III) [Ir(TTP)CH3] effi-
ciently catalyzed N−H insertion reactions of aliphatic and
aromatic amines with different diazoesters (Scheme 1).30 High
INTRODUCTION
■
The biological and medicinal importance of thioethers1,2 drives
the search for convenient and efficient strategies of forming C−
S bonds. Several methods are used to synthesize thioethers,
including use of acid and base catalysts.3−5 Other approaches
involve the use of iron(III) porphyrin catalysts in the addition
of disulfides to olefins,6,7 while alternative routes to thioethers
include palladium-catalyzed coupling of organic halides with
thiols.8,9 Furthermore, thioethers have been produced from
copper-catalyzed reactions between diaryl disulfides and β-
dicarbonyl compounds.10 An atom-economic method of
forming new C−S bonds is the insertion of the carbene
fragment of diazo compounds into the S−H bond of thiols,
releasing N2 as the only byproduct.11 One of the earliest
examples of a diazo reaction with an S−H bond was reported
by Yates, wherein copper was found to catalyze the production
of 1-phenyl-2-(phenylthio)ethan-1-one in 67% yield from the
treatment of benzenethiol with 2-diazoacetophenone at 70
°C.12 Subsequently, transition metal salts and complexes
containing rhenium,13 iron,14 ruthenium,15 scandium,16 in-
dium,17 and rhodium18,19 have been reported to catalyze S−H
insertion reactions with diazo compounds. Catalytic carbene
S−H insertion using porphyrin complexes of iron and
ruthenium has also been demonstrated.20−24
Scheme 1. N−H Insertion Reactions between Diazo Esters
and Amines Catalyzed by Ir(TTP)CH3
catalyst turnover numbers (TON) up to 105 were achieved with
aromatic amine substrates, with near-quantitative yields for
single- and double-insertion products. The proposed active
catalyst (Scheme 2) is a pentacoordinate iridium complex,
Ir(TTP)CH3, 1, that generates an iridium carbene intermediate,
3, on reaction with the diazo reagent. Nucleophilic attack of the
amine substrate on the putative carbene intermediate results in
the formation of an iridium ylide species 4-NH2R, which then
rearranges to form the glycine ester product and the
catalytically active Ir(TTP)CH3.
Despite the vast effectiveness of transition metal complexes
as catalysts in S−H insertion reactions between diazo
compounds and thiols, a more detailed mechanistic inves-
tigation is lacking in the literature. Herein, we show that
A few studies have shown that iridium(III) porphyrins
catalyze X−H insertion reactions (X = C, Si) with diazo
compounds.25−27 Moreover, our group recently reported the
catalytic utility of iridium(III) porphyrinato complexes in
carbene transfer reactions.28−32 Notably, we demonstrated that
Received: December 20, 2016
© XXXX American Chemical Society
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Scheme 2. Proposed Catalytic Cycle for the Previously
Reported Ir(TTP)CH3-Catalyzed Insertion of Carbenes
from Diazoesters into N−H Bonds
Table 1. Reaction of EDA with Aromatic and Aliphatic
Thiols Catalyzed by Ir(TTP)CH3 at 23 °C
a
a
Ir(TTP)CH3 (0.031 μmol; 0.07 mol %), EDA (42.6 μmol; 73 mM),
b
thiol (87.0 μmol; 150 mM), in 0.58 mL of CDCl3. Yields were
determined by NMR with Ph3CH as internal standard. EDA:thiol =
Ir(TTP)CH3 efficiently catalyzes the insertion of carbene
moieties, from diazo esters, into the S−H bond of thiols. In
addition, kinetic studies provide further insight into the reaction
pathway.
c
1:1 (73 mM each).
(Table 1, entries 3 and 4). Similarly, ethyl 2-[(4-chlorophenyl)-
thio]acetate and ethyl 2-[(4-nitrophenyl)thio]acetate were
obtained in 70% and 85% yields from the electron-poor p-
chloro- and p-nitrobenzenethiols, respectively (Table 1, entries
5 and 6). Furthermore, Ir(TTP)CH3 efficiently catalyzed the
reaction of EDA with the aliphatic substrates benzyl mercaptan
and propanethiol, with high S−H insertion yields (Table 1,
entries 7 and 8). In each case, the organic side products were
diethyl maleate and diethyl fumarate.
RESULTS AND DISCUSSION
■
Ir(TTP)CH3-Catalyzed Reactions of Diazo Reagents
with Thiols. When a CDCl3 solution of benzenethiol was
treated with ethyl diazoacetate (EDA) in the presence of a
catalytic amount of Ir(TTP)CH3 (0.07 mol % relative to EDA),
the carbene fragment from EDA readily inserted into the S−H
bond, to generate ethyl 2-(phenylthio)acetate in 87% yield. The
reaction reached completion within 15 min (eq 1, Table 1,
When the bulkier and less active methyl phenyldiazoacetate
(MPDA) was used as the carbene source for a selection of the
thiol compounds (eq 2, X = H), no diazo dimerization was
entry 1), and the only observed byproducts were diethyl
maleate and diethyl fumarate, resulting from carbene
dimerization. In order to minimize this side reaction, the
diazo reagent was added last, in one aliquot. The optimal
stoichiometric ratio was found to be a 2:1 thiol:EDA mole ratio.
In contrast, the use of a 1:1 substrate ratio required longer
reaction times to afford a comparable product yield (Table 1,
entry 2). Typically, reactions were started at −78 °C. After
addition of the diazo reagent, the mixture was allowed to warm
to 23 °C (eq 1) and maintained at this temperature for 15 min.
This reaction protocol is similar to the recently reported
optimized reaction conditions for the Ir(TTP)CH3-catalyzed
single insertion of EDA into the N−H bond of aromatic amines
(Scheme 1).30 Control experiments showed that no reaction
occurred under the optimized conditions in the absence of
Ir(TTP)CH3. The same conditions employed for the S−H
insertion reaction between benzenethiol and EDA were applied
to other aromatic thiols. For example, the yields of thioethers
from the reaction of EDA with the electron-rich p-methyl- and
p-methoxybenzenethiols were 79% and 80%, respectively
observed.28 Thus, treatment of MPDA in separate reactions
with 2-fold excesses of benzenethiol or p-methoxybenzenethiol
and Ir(TTP)CH3 produced the corresponding S−H insertion
products in near-quantitative yields (Table 2, entries 1 and 2).
However, the yield of methyl 2-(benzylthio)-2-phenylacetate
obtained from the 2 h reaction of MPDA with benzyl
mercaptan was much lower (21%), using the same reaction
protocol (Table 2, entry 3). Extending the reaction time to 6 h
increased the yield to 47%. Furthermore, a similarly low
product yield (21%) was obtained when equal amounts of the
substrates were used (Table 2, entry 4). When MPDA was
added first to the catalyst, followed by the addition of benzyl
mercaptan to avoid catalyst poisoning by the thiol,30 the yield
dropped to 5% (Table 2, entry 5). However, use of excess
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Table 2. Reaction of MPDA with Aromatic and Aliphatic
Thiols Catalyzed by Ir(TTP)CH3 at 23 °C
Table 3. Reaction of MTDA with Aromatic and Aliphatic
Thiols Catalyzed by Ir(TTP)CH3
a
a
Yields were determined by NMR, with Ph3CH as an internal
b
standard, based on the amount of limiting reagent. Ir(TTP)CH3
(0.031 μmol), MPDA (42.6 μmol), thiol (87.0 μmol), in 0.58 mL of
c
a
CDCl3. Ir(TTP)CH3 (0.031 μmol), MPDA (42.6 μmol), thiol (42.6
Ir(TTP)CH3 (0.306 μmol; 0.72 mol %), MTDA (42.6 μmol; 73
d
μmol), in 0.58 mL of CDCl3. MPDA was added first to Ir(TTP)CH3.
mM), thiol (87.0; 150 mM), in 0.58 mL of CDCl3. Yields were
e
b
Ir(TTP)CH3 (0.031 μmol), MPDA (87.8 μmol), thiol (35.4 μmol),
determined by NMR, with Ph3CH as internal standard. Reaction
f
c
d
in 0.50 mL of CDCl3. Ir(TTP)CH3 (0.031 μmol), MPDA (227
times at 23 °C. Synthesized at −78 °C. Isolated yields (in
μmol), thiol (35.4 μmol), in 0.50 mL of CDCl3.
parentheses) based on the amount of MTDA.
amounts of MPDA (added last) at 2.5 and 6.4 equiv relative to
benzyl mercaptan was found to improve the product yields to
80% and 83% (Table 2, entries 6 and 7). This also enhanced
the reaction rates, but also led to an increase in side products.
The carbene moiety of methyl (p-tolyl)diazoacetate
(MTDA) also inserts into the S−H bond of thiols, albeit
needing a higher catalyst loading than was used with ethyl
diazoacetate (EDA) and MPDA (eq 2, X = CH3). Using the
same reaction protocol that was employed above, methyl 2-
(phenylthio)-2-(p-tolyl)acetate was obtained from the reaction
of benzenethiol with MTDA in 61% yield within 1 h (Table 3,
entry 1). Similar treatment of other aromatic and aliphatic
thiols with MTDA in the presence of catalytic amounts of
Ir(TTP)CH3 gave the corresponding thioethers in yields up to
81% (Table 3, entries 2−7).
Equilibrium Binding of Thiols to Ir(TTP)CH3 at 23 °C.
During our previously reported Ir(TTP)CH3-catalyzed in-
sertion of carbenes, from diazo reagents, into N−H bonds,
catalyst inhibition by the amine substrates was observed
(Scheme 2).30 In that study, a reduction in the rate of N−H
insertion was observed as the aniline concentration was
increased from 0.0595 M to 0.209 M, with initial concen-
trations of [Ir(TTP)CH3]0 = 8.92 μM and [MDA]0 = 0.117 M.
This inhibition was due to the reversible coordination of amine
substrates to the five-coordinate iridium complex. The
possibility of a similar thiol binding to Ir(TTP)CH3 was
studied by titration experiments, using UV−visible spectropho-
tometry (eq 3; see Experimental Section). The equilibrium
binding constants (Table 4) generated a Hammett plot (Figure
1) that provided a ρ+ constant of −0.18 0.01. The negative ρ+
value indicates that electron-rich thiols are more tightly bound
to iridium than electron-poor thiols. This trend is similar to that
reported earlier for anilines,30 although primary aromatic thiols
are less strongly bound (Kb = 4.25 × 102 to 7.98 × 102) to
Table 4. Binding Constants for the Coordination of Thiols
to Ir(TTP)CH3 in benzene at 23 °C
entry
thiol
K
1
2
3
4
5
6
p-methoxybenzenethiol
p-methylbenzenethiol
benzenethiol
(7.98 0.02) × 102
(6.76 0.24) × 102
(5.78 0.33) × 102
(5.26 0.35) × 102
(4.25 0.44) × 102
(1.69 0.029) × 103
p-chlorobenzenethiol
p-nitrobenzenethiol
benzyl mercaptan
Figure 1. Hammett correlation for the equilibrium binding of para-
substituted benzenethiols to Ir(TTP)CH3 at 23 °C.
C
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Ir(TTP)CH3 than are aromatic amines (Kb = 2.5 × 103 to 2.5 ×
105).
Mechanistic Studies. Substrate Competition Experi-
ments. Competition experiments involving benzenethiol and
various para-substituted benzenethiols were carried out to
determine relative rates (eq 4, Table 5). With MDA, a
Figure 2. Hammett correlations from competition reactions between
benzenethiol and p-substituted benzenethiols in the presence of a
catalytic amount of Ir(TTP)CH3 and either MDA or MTDA.
Hammett constant of ρ = −0.12 0.01 was obtained, while a
value of ρ = −0.78 0.11 was found for reactions with MTDA
(Figure 2). A value of ρ = −0.66 was previously observed
during insertion reactions of EDA into the N−H bond of
anilines, catalyzed by iron(III)tetraphenylporphyrin chloride
[Fe(TPP)Cl],33 while a ρ+ value of −0.56 was reported during
the Ir(TTP)CH3-catalyzed insertion reactions of MPDA into
the N−H bond of anilines.30
Trapping a Sulfonium Ylide Intermediate. In the Ir(TTP)-
CH3-catalyzed S−H insertion reaction, the negative Hammett ρ
values suggest a buildup of positive charge on the sulfur atom
during the S−H insertion reactions, consistent with the
formation of a metal−ylide species. In analogy, a metal-
bound ylide intermediate was recently suggested for a
dirhodium-catalyzed S−H insertion with diazo reagents.34
More recently, in a myoglobin-catalyzed insertion of carbenes
from diazo esters into the S−H bonds of thiols, Fasan and co-
workers used allyl phenyl sulfide to trap a proposed sulfonium
ylide intermediate.35 The putative metal−ylide intermediate
rapidly rearranged by an intramolecular 2,3-sigmatropic process
via intermediate I (Scheme 3).35 Similarly, treatment of a
catalytic amount of Ir(TTP)CH3 with a CDCl3 solution of allyl
phenyl sulfide and EDA under the same conditions as those for
the thiol insertion reactions (see Experimental Section for
details) resulted in the formation of 2-(phenylthio)pent-4-
enoate (II) in 85% yield, in addition to carbene dimers from
EDA (4%). The formation of II further supports a metal-bound
ylide intermediate in the current Ir(TTP)CH3-catalyzed S−H
insertion reactions.
a
Table 5. Substrate Competition Reactions Catalyzed by Ir(TTP)CH3
a
b
The reagents and catalyst were added together at −78 °C; then the mixture was allowed to warm to 23 °C over a period of 1 h. Ir(TTP)CH3
(0.031 μmol), substrate A (42.6 μmol), Substrate B (42.6 μmol), diazo reagent (46.8 μmol), in 0.58 mL of CDCl3. Product ratios were determined
by NMR, with Ph3CH as internal standard.
D
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Scheme 3. Allyl Sulfide Trapping of Ylide Intermediate I
tolylthio)acetate] versus time (see the Supporting Informa-
tion). As the catalyst concentration was varied with the same
initial concentrations of the thiol (0.207 M) and MDA (0.072
M), the initial reaction rate increased linearly with the rise in
the catalyst concentration (Table 6). The order of reaction with
Table 6. Initial S−H Insertion Rates for eq 5 with Various
Isotope Effect. Using a 1:1 mixture of p-methoxybenzene-
thiol (CH3OC6H4SH) and monodeuterated p-methoxybenze-
nethiol (CH3OC6H4SD) as substrates, in the presence of either
MDA or MPDA, kinetic isotope effects (KIEs) were studied
(Table 5). A KIE of 1.08 0.03 was observed with MDA as the
carbene source, while the KIE was 1.15 0.03 when the diazo
compound was MPDA. In the previous Ir(TTP)CH3-catalyzed
N−H insertion study, KIEs of 1.0 0.2 and 2.7 0.2 were
reported when the carbene sources were EDA and MPDA,
respectively.30 Adams also reported a small kinetic isotope
effect (KIE = 1.2) during Rh(OAc)4-catalyzed intramolecular
C−H insertions with 1-methyl-1-(diazoacety1)cyclohexane.36
In the current work, the observed KIEs, albeit small in
magnitude, are consistent with a putative iridium-sulfonium
ylide intermediate (Scheme 4).
a
Ir(TTP)CH3 Concentrations, at 298 0.4 K
entry
[Ir(TTP)CH3] (μM)
rate (μM/s)
1
2
3
4
5
3.08
4.84
6.15
12.3
24.6
15.2
16.4
40.2
77.2
133
a
[MDA]0 = 0.072 M and [p-methylbenzenethiol]0 = 0.207 M.
respect to catalyst concentration was derived from a plot of
log(initial rate) vs log[Ir(TTP)CH3]. The slope of this plot
(Figure S8) showed that the rate order with respect to catalyst
concentration was 1.12 0.17.
The reaction rate dependence on MDA concentration was
explored in a similar manner (Table 7) with [Ir(TTP)CH3]0 =
Scheme 4. Proposed Catalytic Cycle for the Ir(TTP)CH3-
Catalyzed Insertion of Carbenes from Diazoesters into S−H
Bonds
Table 7. Initial S−H Insertion Rates for Eq 5 with Various
a
MDA Concentrations at 298 0.5 K
entry
[MDA] (M)
rate (μM/s)
1
2
3
0.036
0.072
0.144
30.0
77.2
141.9
a
[Ir(TTP)CH3]0 = 1.23 × 10−5 M and [p-methylbenzenethiol]0 =
0.207 M.
1.23 × 10−5 M and [thiol]0 = 0.207 M. The plot of the
log(initial rate) vs log[MDA] exhibited a slope of 1.12 0.14,
consistent with a rate law that is first order in [MDA] (Figure
S9). A similar first-order diazo dependence was found
previously during the Ir(TTP)CH3-catalyzed cyclopropanation
of 1-hexene with MDA.28
Furthermore, a series of kinetic runs were performed with
various p-methylbenzenethiol concentrations, with the same
initial concentrations of MDA (7.20 × 10−2 M) and
Ir(TTP)CH3 (1.23 × 10−5 M) at 298 K (Table 8). In general,
the initial rates span a small range that corresponds to a small
fractional [thiol] rate order of 0.3 0.1, determined from a plot
of log(initial rate) vs log[thiol] (Figure 3).
Hammett plots, kinetic data, and ylide-trapping experiments
support the proposed catalytic cycle shown in Scheme 4, which
is similar to that proposed for the iridium-catalyzed N−H
insertion with amines and diazo compounds (Scheme 2).30
Reversible thiol ligation to the iridium metal center, as
demonstrated by binding experiments, forms an inactive
hexacoordinated (thiol)Ir(TTP)CH3 (2-RSH). Upon dissoci-
ation of thiol, diazo binding to the five-coordinate iridium
center generates an iridium−carbene complex (3).
Kinetic Studies. Kinetic studies were undertaken to gain
further mechanistic insights into the S−H insertion reaction.
For ease of monitoring by 1H NMR, p-methylbenzenethiol was
used as the thiol substrate and methyl diazoacetate (MDA) was
the carbene source (eq 5). The initial reaction rate (first 10% of
reaction) was determined for each kinetic run from a plot of the
concentration of the S−H insertion product [methyl 2-(p-
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Table 8. Initial Rates of S−H Insertion for Eq 5 with Various
a
Thiol Concentrations
entry
[Thiol]:[MDA]
[Thiol] (M)
rate (μM/s)
1
2
3
4
5
6
7
0.71:1
1.44:1
2.88:1
5.79:1
7.92:1
16.9:1
22.9:1
0.0513
0.104
0.207
0.414
0.570
1.22
59.0
63.4
77.2
111
124
177
1.65
151
a
MDA (0.072 M), Ir(TTP)CH3 (1.23 × 10−5 M) in CDCl3 at 298.0
Figure 4. First-order [RSH] plot from eq 11.
0.36 K.
[Ir(TTP)CH3]0 = [Ir(TTP)CH3] + [Ir(TTP)CH3(RSH)]
(7)
[Ir(TTP)CH3]0
1 + K[RSH]
[Ir(TTP)CH3] =
(8)
Rate = k[Ir(TTP)CH3][MDA][RSH]n
(9)
k[Ir(TTP)CH3]0[MDA][RSH]n
Rate =
1 + K[RSH]
(10)
Figure 3. Log(initial rate) vs log(thiol) plot for [thiol] rate order for
eq 5. Initial concentrations: [p-methylbenzenethiol]0 = 0.0513−2.09
M, [MDA]0 = 0.072 M, and [Ir(TTP)CH3]0 = 1.23 × 10−5 M in
CDCl3 at 298 0.4 K.
Rate(1 + K[RSH])
= k[RSH]n
[MDA][Ir(TTP)CH3]0
(11)
The relatively high binding constant of allyl phenyl sulfide to
Ir(TTP)CH3 (K = (9.01 0.12) × 103; Figure S7) suggested
that the thioether products might inhibit the reactions (eq 2).
Thus, methyl 2-(p-tolylthio)acetate, a product of the reaction of
MDA with p-methylbenzenethiol, was probed as a possible
inhibitor. In reactions at 298 K with [Ir(TTP)CH3] = 1.23 ×
10−5 M, [p-methylbenzenethiol]0 = 0.207 M, and [MDA]0 =
0.072 M, the initial rates were 77.9 and 77.2 μM/s with and
without the addition of 28.2 mM of the thioether, respectively.
Thus, the presence of product had no effect on the initial
reaction rate and it must not significantly bind to the Ir catalyst
under the reaction conditions.
Nucleophilic attack of the thiol on the metal−carbene
complex produces a sulfonium ylide complex (4-RSH), which
undergoes rearrangement to form the S−H insertion product
and regenerate the Ir(TTP)CH3 catalyst (1). Ylide formation is
consistent with the buildup of positive charge on sulfur, as
demonstrated with competition experiments and by ρ values of
−0.12 and −0.78, obtained from Hammett plots (Figure 2,
[thiol] = 0.15 M).
Derivation of a complete rate law based on the molecular
steps shown in Scheme 4 is complicated by the dual roles of the
thiol-inhibitory binding to Ir(TTP)CH3 and nucleophilic attack
on the carbene complex 3. However, the equilibrium binding
constant of the thiol to Ir(TTP)CH3 can be utilized to calculate
the amount of active catalyst, that is, complex 1, that has no
thiol associated with it. Combining the equilibrium binding
expression (eq 6) with the sum of the amount of iridium
complexes (eq 7) yields the amount of active catalyst 1 (eq 8).
The simplified rate law is expressed by eq 9, where the rate
orders for [Ir(TTP)CH3] and [MDA] have already been
established as 1 and the order in [RSH] remains to be
determined. Substitution of eq 8 into eq 9 gives the rate law (eq
10) expressed in known quantities. Rearranging eq 10 to eq 11
and plotting rate(1 + K[RSH])/([Ir(TTP)CH3]0[MDA]) vs
[RSH] affords a straight line (Figure 4), establishing the rate
order of [RSH] in eq 9 to be first order (n = 1). This rate law
(eq 9, n = 1) indicates that the transition state resembles ylide
complex 4 and that attack of the thiol on the carbene complex
is the rate-determining step.
CONCLUSIONS
■
The results of this work demonstrate the effectiveness of
(5,10,15,20-tetratolylporphyrinato)methyliridium(III) in the
catalytic insertion of carbenes derived from diazo esters into
the S−H bond of aromatic and aliphatic thiols. Notable features
of this system include (1) the use of low catalyst loadings
(0.07−0.7 mol %), (2) low reaction temperatures (−78 and 23
°C), (3) short reaction times (15−75 min with EDA), and (4)
no need for slow addition of either the diazo ester or the thiol.
The predominant form of the iridium complex in the
reaction mixture is a coordinatively saturated species, (thiol)-
Ir(TTP)CH3. Thus, the equilibrium binding of thiol substrates
to iridium inactivates the metal and overshadows the catalytic
process. However, a more informative view of the catalytic cycle
can be obtained by focusing the kinetic treatment on the true
amount of catalytically active five-coordinate complex, Ir-
(TTP)CH3 (1, Scheme 4), present in solution. In this case, the
simplified rate law is found to be first order in each of the
concentrations of thiol, diazo reagent, and Ir(TTP)CH3 (eq 9,
n = 1). This indicates that the transition state contains all three
components (with the exception of N2, which is rapidly lost)
and that the turnover-limiting step is the nucleophilic attack of
[Ir(TTP)CH3(RSH)]
[Ir(TTP)CH3][RSH]
K =
(6)
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silica gel chromatography, the volatiles were removed under reduced
pressure, to afford the thioether product, which was characterized as
described below.
thiol on the carbene complex, 3, to generate the ylide
intermediate, 4-RSH. Competition and trapping experiments
also provide evidence for an ylide intermediate, which then
undergoes rapid rearrangement to form the thioether product
and regenerate the active Ir catalyst. This more detailed
mechanistic picture should provide insight for further develop-
ment of new catalysts and C−S bond forming processes.
Methyl 2-((4-Methoxyphenyl)thio)-2-(p-tolyl)acetate. The reac-
tion mixture was stirred at ambient temperature for 30 min, then
purified by silica gel chromatography (16.0 cm length × 0.15 cm
diameter), using 30:1 hexanes/ethyl acetate as eluent. The product
was obtained as an orange solid. Yield: 74% (40.7 mg, 0.135 mmol).
Anal. Calcd for C17H18O3S: C, 67.52; H, 6.00. Found: C, 67.68; H,
5.87. 1H NMR (600 MHz, CDCl3) δ: 2.33 (s, 3H), 3.66 (s, 3H), 3.79
(s, 3H), 4.75 (s, 1H), 6.81 (m, 2H), 7.13 (d, 2H, 3JHH = 6.0 Hz), 7.30
EXPERIMENTAL SECTION
■
General Considerations. All manipulations were performed
under a dry nitrogen atmosphere, in a glovebag, or in air, except
where otherwise stated. Ir(TTP)CH3,37 MDA,38 MPDA,39 and
MTDA40 were prepared according to literature procedures.
CH3OC6H4SD was prepared by treating a THF solution of p-
methoxybenzenethiol with D2O for 24 h. Removal of volatiles under
reduced pressure afforded CH3OC6H4SD as a viscous oil, which was
3
(d, 2H, JHH = 6.0 Hz), 7.34 (m, 2H). 13C NMR (151 MHz, CDCl3)
δ: 21.47, 52.84, 55.59, 57.45, 114.78, 124.17, 128.72, 129.60, 133.02,
136.38, 138.33, 160.45, 171.44. HRMS (+ESI): calcd for [MH]+
(C17H19O3S)+ m/z 303.1055; found m/z 303.1043.
Methyl 2-((4-Nitrophenyl)thio)-2-(p-tolyl)acetate. The reaction
mixture was stirred at ambient temperature for 30 min, then purified
by silica gel chromatography (17.0 cm length × 0.15 cm diameter),
using 30:1 hexanes/ethyl acetate as eluent. The product was obtained
1
stored in a desiccator prior to use. H NMR analysis revealed 80%
deuterium incorporation. CDCl3 and C6H6 were stored over 4 Å
molecular sieves prior to use, while acetonitrile and dichloromethane
were deoxygenated and dried by passage through columns of reduced
copper and alumina, respectively. All other chemicals were reagent
grade and used without further purification. Absorption spectra were
acquired on an Agilent Cary 8454 UV−vis spectrophotometer. Kinetic
NMR spectra were acquired using a Bruker DRX 400 MHz
spectrometer, while other NMR spectra were collected using Varian
1
as a yellow solid. Yield: 57% (33.0 mg, 0.104 mmol). H NMR (600
MHz, CDCl3) δ: 2.35 (s, 3H), 3.73 (s, 3H), 5.10 (s, 1H), 7.18 (d, 2H,
3JHH = 6.0 Hz), 7.38 (m, 4H), 8.10 (d, 2H, 3JHH = 6.0 Hz). 13C NMR
(151 MHz, CDCl3) δ: 21.50, 53.51, 54.51, 124.31, 128.59, 129.10,
130.11, 131.43, 139.28, 144.92, 146.42, 170.44. HRMS (+ESI): calcd
for [MH]+ (C16H16NO4S)+ m/z 318.0800; found m/z 318.0793.
Methyl 2-((4-Methylphenyl)thio)-2-(p-tolyl)acetate. To minimize
azine formation,29,44 the reaction of 4-methylbenzenethiol with
MTDA was carried out using the same method outlined above, but
at −78 °C for 2 h. The product was purified by silica gel
chromatography (7 cm length × 0.22 cm diameter), using 45:1
hexanes/ethyl acetate as eluent. The product was obtained as a red oil.
Yield: 30% (15.6 mg, 0.0543 mmol). 1H NMR (400 MHz, CDCl3) δ:
2.31 (s, 3H), 2.32 (s, 3H), 3.64 (s, 3H), 4.73 (s, 1H), 7.12 (m, 8H).
13C NMR (101 MHz, CDCl3) δ: 21.51, 21.52, 52.96, 56.73, 128.68,
129.68, 130.05, 130.30, 133.43, 134.72, 136.90, 138.44, 138.59. HRMS
(+ESI): calcd for [MH]+ (C17H19O2S)+ m/z 287.1106; found m/z
287.1094.
1
MR 400 MHz and Bruker AVIII 600 MHz spectrometers. H NMR
peak positions were referenced against residual proton resonances of
deuterated CDCl3 (δ 7.26 ppm). Products of S−H insertion reactions
were identified by comparing their 1H NMR spectra with those found
in the literature.10,13,34,35,41−43 Previously unreported S−H insertion
products obtained from reactions with MTDA were isolated and
characterized by NMR, elemental analysis, and HR-MS.
General Procedure for the Ir(TTP)CH3-Catalyzed Reactions
of Diazo Esters with Thiols. In air, a CH2Cl2 solution (130 μL) of
Ir(TTP)CH3 (0.0310 μmol) was transferred via syringe from a 0.236
mM stock solution of the catalyst into an NMR tube. The solution was
then taken to dryness in the NMR tube under a flow of nitrogen gas. A
CDCl3 solution (50.0 μL) of triphenylmethane (31.1 μmol) was then
added as an internal standard, from a 622 mM stock solution. This was
followed by addition of the thiol (87.0 μmol) in 0.410 mL of a CDCl3
solution (212 mM). The NMR tube was then capped with a rubber
septum, and it was cooled with its contents to −78 °C in a dry ice/
acetone bath. After ca. 10 min, EDA (42.6 μmol) was added by
injecting 0.120 mL of a CDCl3 solution (355 mM) through the rubber
septum. After an additional 5 min at −78 °C, the reaction mixture was
allowed to warm to ambient temperature. 1H NMR was used to
monitor the reaction and to determine product yields. When the diazo
compound was MPDA or MTDA, stock solutions of the reagents were
added using the amounts specified in the footnotes of Table 2 or 3.
General Procedure for Substrate Competition Experiments.
The same procedure above was followed, but the benzenethiol and p-
substituted benzenethiol or CH3OC6H4SH and CH3OC6H4SD for
each reaction were premixed in a 1:1 mol ratio and introduced into the
NMR tube, as a single solution containing 42.6 μmol of each thiol. The
diazo reagent (46.8 μmol) was added after the NMR tube and its
contents had been cooled to −78 °C.
Procedure for the Preparation of New Thioethers. From a
2.32 mM stock solution of Ir(TTP)CH3 in CH2Cl2, a 0.590 mL
aliquot containing 1.37 μmol of catalyst was transferred via syringe
into a 25 mL round-bottomed flask. The flask was charged with p-
methoxy- or p-nitrobenzenethiol (0.370 mmol), 1.1 mL of CH2Cl2,
and a stir bar, then capped with a rubber septum, through which a
syringe needle attached to a nitrogen-filled balloon was inserted. The
flask and its contents were then cooled to −78 °C in a dry ice/acetone
bath. After about 10 min, a CHCl3 solution (0.85 mL) containing
0.181 mmol of MTDA was injected into the flask through the rubber
septum. After an additional 5 min at −78 °C, the reaction mixture was
allowed to warm to ambient temperature, and stirring was continued at
this temperature for the specified time below. After purification by
Methyl 2-((4-Chlorophenyl)thio)-2-(p-tolyl)acetate. To minimize
azine formation,29,44 the reaction of 4-chlorobenzenethiol with MTDA
was carried out using the same method outlined above, but at −78 °C
for 2 h. The product was purified by silica gel chromatography (17 cm
length × 0.15 cm diameter), using 40:1 hexanes/ethyl acetate as
eluent. The product was obtained as a red oil. Yield: 33% (18.3 mg,
1
0.0597 mmol). H NMR (400 MHz, CDCl3) δ: 2.32 (s, 3H), 3.65 (s,
3H), 4.72 (s, 1H), 7.11 (m, 2H), 7.19 (m, 4H), 7.24 (m, 2H). 13C
NMR (101 MHz, CDCl3) δ: 21.51, 53.11, 56.33, 128.64, 129.40,
129.78, 130.01, 134.29, 134.58, 135.96, 138.71. HRMS (+ESI): calcd
for [MK]+ (C16H15ClKO2S)+ m/z 345.0119; found m/z 345.0300.
Reaction between Allyl Phenyl Sulfide and EDA in the
Presence of Ir(TTP)CH3. A procedure similar to those used for
carbene insertion into S−H bonds was followed, but with the use of
0.031 μmol of Ir(TTP)CH3, 44.1 μmol (65.8 mM) of EDA, 147 μmol
(219 mM) of allyl phenyl sulfide, and 6.58 μmol of mesitylene as an
internal standard.
General Procedure for Kinetic Experiments. From a 0.236 mM
stock solution of Ir(TTP)CH3 in CH2Cl2, a 32.5 μL aliquot containing
0.00767 μmol of Ir(TTP)CH3 catalyst was transferred via syringe into
an NMR tube, then dried under a flow of nitrogen gas. To the dried
catalyst was then added 50.0 μL of a CDCl3 solution (622 mM)
containing triphenylmethane (31.1 μmol), followed by an aliquot of p-
methylbenzenethiol (33.3 μmol to 1.36 mmol) in CDCl3. The NMR
tube was then capped with a rubber septum, and a syringe needle
attached to a nitrogen-filled balloon was inserted through the septum.
Immediately prior to insertion of the sample into a shimmed NMR
probe that was equilibrated to 298 K, MDA (46.8 μmol) was added
using 50 μL of a CDCl3 solution (936 mM). After rapid and thorough
mixing, the NMR tube was inserted into the NMR instrument, and
acquisition of spectra at 16 s intervals began as quickly as possible.
Determination of Binding Constants of Thiols and Allyl
Phenyl Sulfide to Ir(TTP)CH3. Binding constants were measured
G
DOI: 10.1021/acs.organomet.6b00947
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
using an adapted method of a previously published procedure.30 All
absorbance spectra were acquired in quartz sample cells with a 1 mm
path length, and freshly prepared benzene solutions of thiols or allyl
phenyl sulfide were used in all measurements. The extinction
coefficients of Ir(TTP)CH3 were determined at 400 and 425 nm
from the absorbance spectrum of an 80 μM benzene solution. A 200-
fold excess of ligand was used to obtain the extinction coefficients (see
Table S1) for the hexacoordinated (RSH)Ir(TTP)CH3 or (RSR′)Ir-
(TTP)CH3 complexes, using solutions containing 80 μM Ir(TTP)-
CH3 and 17 mM of the desired thiol or sulfide. Equilibrium constants
were measured from absorbance spectra of solutions with known
initial concentrations of Ir(TTP)CH3 (80 μM) and thiols or sulfide
(25.3 μM to 7.21 mM).
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.6b00947.
(25) Wang, J. C.; Xu, Z. J.; Guo, Z.; Deng, Q. H.; Zhou, C. Y.; Wan,
X. L.; Che, C. M. Chem. Commun. 2012, 48, 4299.
(26) Lopez-Sanchez, C.; Alvarez-Corral, M.; Munoz-Dorado, M.;
Rodriguez-Garcia, I. Synlett 2012, 23, 2469.
(27) Wang, J. C.; Zhang, Y.; Xu, Z. J.; Lo, V. K. Y.; Che, C. M. ACS
Catal. 2013, 3, 1144.
■
S
(28) Anding, B. J.; Ellern, A.; Woo, L. K. Organometallics 2012, 31,
3628.
(29) Anding, B. J.; Brgoch, J.; Miller, G. J.; Woo, L. K.
Organometallics 2012, 31, 5586.
(30) Anding, B. J.; Woo, L. K. Organometallics 2013, 32, 2599.
(31) Dairo, T. O.; Ellern, A.; Angelici, R. J.; Woo, L. K.
Organometallics 2014, 33, 2266.
UV−vis titration spectra for thiol binding to Ir(TTP)-
CH3, extinction coefficients for Ir(TTP)CH3(thiol)
1
complexes, kinetic plots for determining rate law, H
and 13C NMR spectra for new thioether products (PDF)
AUTHOR INFORMATION
■
(32) Anding, B. J.; Ellern, A.; Woo, L. K. Organometallics 2014, 33,
2219.
(33) Baumann, L. K.; Mbuvi, H. M.; Du, G.; Woo, L. K.
Organometallics 2007, 26, 3995.
(34) Xu, B.; Zhu, S. F.; Zhang, Z. C.; Yu, Z. X.; Ma, Y.; Zhou, Q. L.
Chem. Sci. 2014, 5, 1442.
Corresponding Author
*E-mail: kwoo@iastate.edu.
ORCID
L. Keith Woo: 0000-0002-4541-2274
Notes
(35) Tyagi, V.; Bonn, R. B.; Fasan, R. Chem. Sci. 2015, 6, 2488.
(36) Wang, P.; Adams, J. J. Am. Chem. Soc. 1994, 116, 3296.
(37) Yeung, S. K.; Chan, K. S. Organometallics 2005, 24, 6426.
(38) Mao, H. B.; Lin, A. J.; Shi, Y.; Mao, Z. J.; Zhu, X. B.; Li, W. P.;
Hu, H. W.; Cheng, Y. X.; Zhu, C. J. Angew. Chem., Int. Ed. 2013, 52,
6288.
(39) Zhao, W. J.; Yan, M.; Huang, D.; Ji, S. J. Tetrahedron 2005, 61,
5585.
(40) Davies, H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
NSF grant CHE-0809901 provided partial support for this
work. We also thank Dr. A. Bakac for substantial help with
kinetics treatments and Prof. R. J. Angelici for many helpful
discussions.
2000, 122, 3063.
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DOI: 10.1021/acs.organomet.6b00947
Organometallics XXXX, XXX, XXX−XXX