Mobilizing Cu(I) for carbon-carbon bond forming catalysis in the presence of thiolate. Chemical mimicking of metallothioneins

Article abstract of DOI:10.1021/ja200792m

Copper(I) is rendered catalytically viable in the presence of thiolate by the design of a small molecule chemical analogue of the metallothionein system in which an N-O reactant serves the same conceptual purpose of the S-S reactant of the biological system.

Full text of DOI:10.1021/ja200792m

ARTICLE
pubs.acs.org/JACS
Mobilizing Cu(I) for CarbonꢀCarbon Bond Forming Catalysis in the
Presence of Thiolate. Chemical Mimicking of Metallothioneins
Zhihui Zhang,† Matthew G. Lindale, and Lanny S. Liebeskind*
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
S Supporting Information
b
ABSTRACT: Copper(I) is rendered catalytically viable in the presence of thiolate
by the design of a small molecule chemical analogue of the metallothionein system
in which an NꢀO reactant serves the same conceptual purpose of the SꢀS reactant
of the biological system.
’ INTRODUCTION
carbonꢀcarbon bond forming processes that take place between
thioorganic substrates and boronic acids (Figure 1). The “first-
generation” of the copper-mediated, desulfitative reaction systems
proceeds under anaerobic conditions, and is catalyzed by Pd and
Metal binding proteins are essential to many life-sustaining
processes. The nonthermodynamic binding selectivity and specificity
of metals to proteins in living systems have captured the focus of much
research effort.1 Equally essential to life-sustaining processes are the
biomolecular mechanisms by which tightly bound metals are selec-
tively transferred1b,3 or released3 from a thermodynamically strong
coordination sphere within a protein. As mechanistic knowledge of
these metal mobilizing biological processes is uncovered, occasions
may arise for translating the biological processes into ones useful in
chemical catalysis in the laboratory. In particular, the biomolecular
mechanisms by which Nature releases catalytically important thio-
philic metals like Cu from high-sulfur binding sites within proteins
should be useful points of inspiration from which to develop novel
preparative protocols where the catalytic turnover of a thiophilic metal
in a sulfur-containing environment is essential. Opportunities for
productive metal catalysis in sulfur-rich systems are found in energy-
related research (metal-catalyzed desulfurization of carbon-based
fuels),4 detoxification of nerve gas agents (metal-catalyzed transfor-
mations of phosphonothioate and phosphorothioates),5 and in the
synthesis of fine chemicals through desulfitative transformations.6
As a case in point, consider the metallothioneins, ubiquitous small
proteins capable of binding up to 7 equivalents of mono- and divalent
metals such as Cu(I) and Zn(II), among others.7 Significant insights
into the triggered release of Zn and Cu from the cysteine-rich
coordination spheres resident within metallothioneins have been
obtained.3a,b,9 Although positioned within a tightly binding thiol/
thiolate-rich ligand environment, the thiophilic metal is rapidly
released when a metallothionein is exposed to an exogenous
disulfide3f,10 or to related reagents,3b,d or to NO.3c,11 Following one
of these leads we describe herein a novel Cu(I)-catalyzed reaction
system that finds its specific inspiration in the mild S-centered
oxidative release of metal from the high cysteine coordination sphere
of the metallothioneins upon exposure to an exogenous disulfide.
Copper is an essential element in biology, and it also plays a central
role in many modern metal-mediated organic transformations.11 In
particular, by virtue of its thiophilicity and accessible multiple
oxidation states, it is a key metal in new pH-neutral, desulfitative
enabled by stoichiometric quantities of a Cu(I) carboxylate.6a,13
A
newer second-generation system takes place under aerobic reaction
conditions, is palladium-free, and uses only catalytic quantities of
Cu.13 Organostannanes are also effective partners in desulfitative
couplings.6a,15
While the anaerobic and aerobic desulfitative coupling protocols
superficially appear to be quite different, they share two common
aspects that are essential to Cu-catalysis in a thiophilic environment.
In each case (1) the thiolate is fully scavenged from the reaction
system and (2) the boronic acid ꢀB(OH)2 moiety is provided with
a thermodynamically strongly bonding “oxygenate” ligand for its
third valence. These characteristics of the desulfitative coupling
reactions are jointly satisfied in the first generation versions of the
desulfitative chemistry through the use of stoichiometric quantities
of the copper carboxylate source:6a,14a the CuI scavenges the thiolate
and the carboxylate serves as the third valence for ꢀB(OH)2. The
second generation aerobic reactions mentioned above proceed with
only catalytic quantities of Cu, but they require a sacrificial second
equivalent of the boronic acid. Under the aerobic reaction condi-
tions this second equivalent of the boronic acid serves to scavenge
the thiolate from the reaction cycle as a nonperturbing thio ether.
The aerobic reaction parameters of the second generation desulfi-
tative couplings also provide the “oxygenate” moiety, derived from
O2, that pairs with the ꢀB(OH)2 moiety.
This mechanistic understanding of the first and second generation
thioorganic-boronic acid desulfitative coupling reactions raises an
interesting challenge: “Can the desulfitative coupling of a thioorganic
and a boronic acid be achieved using only catalytic quantities of Cu
and without squandering an extra equivalent of the boronic acid?”
The biological metallothionein system mentioned above suggests a
solution to the catalytic challenge of the chemical system. Within a
Received: January 26, 2011
Published: March 30, 2011
r
2011 American Chemical Society
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Figure 1. First and second generation desulfitative coupling of thioorganics and boronic acids.
Scheme 1
Scheme 2. The Metallothionein Mimic Concept
metallothionein, exposure of a metal-bound thiolate ligand to an
exogenous disulfide converts the strongly binding thiolate to a weakly
binding disulfide ligand,15 thereby liberating the metal from the
protein through an S-centered oxidation (Scheme 1).
(4-methoxyphenyl)tri-n-butylstannane or 4-(formylphenyl) boronic
acid were exposed to varying amounts of CuI-3-methylsalicylate
(CuMeSal17) in DMF at various temperatures under argon. In most
cases the boron and the tin reagents showed similar reactivity trends.
Desulfitative coupling performed at 60 °C is facile for the E-oxime
stereoisomer (Table 1, entries 1ꢀ4), but the process at this
temperature is strictly stoichiometric in Cu (recovery of the Z-oxime
reflects the mass balance). Catalytic turnover of Cu ensues at 100 °C,
although recovery of the unreactive Z-oxime at this temperature still
minimizes the reaction efficiency (Table 1, entries 5 and 6).
Reactions were noticeably faster using microwave irradiation
(Table 1, entries 7ꢀ10), with the fastest reactions and full conversion
of both the E- and the Z-oxime stereoisomers taking place within 1 h
at 150 °C. Under these conditions the desired ketone and the
anticipated benzoisothiazole were obtained in a roughly 1:1 ratio.
Control experiments demonstrated that both the Cu and the
internal O-methyl oxime moiety are essential for catalytic turnover.
In the absence of Cu under microwave heating at 150 °C the thiol
ester 3a did not generate ketone from either the stannane or the
boronic acid reactant (Table 1, entries 11 and 12). Furthermore, the
thiol ester 3a was surprisingly robust under microwave heating at
150 °C in the absence of the boron or tin reactant, even in the
presence of the Cu catalyst (Table 1, entry 13).
The importance of the internal O-methyl oxime moiety for
catalytic turnover was highlighted through a series of experiments.
Exposure of the simple thiol ester p-tolyl(CO)S-p-tolyl to (4-
methoxyphenyl)tri-n-butylstannane in the presence of 20 mol %
CuMeSal under microwave heating at 150 °C generated a small
amount (17%) of the ketone (Table 1, entry 14), while an analogous
reaction with 4-(formylphenyl) boronic acid showed no evidence of
reaction with simple thiol esters (Table 1, entry 15). The former
result demonstrates, at least at the elevated reaction temperatures
under study, that the stannane system does not require the presence
of the internal oxime function to facilitate coupling with the thiol ester,
but under the conditions explored the transformation to ketone
appears to be stoichiometric, not catalytic in Cu. As a control
experiment to assess the importance of the internal oxime moiety
as both a Cu-thiolate trapping agent and an oxygenate partner for
Cu(I) in the catalytic cycle, p-tolyl(CO)S-p-tolyl and both (4-
methoxyphenyl)tri-n-butylstannane and 4-(formylphenyl) boronic
To render Cu(I) catalytically viable in a desulfitative chemical
transformation without sacrificing a second equivalent of the
boronic acid coupling agent, a small molecule analogue of the
metallothionein system was designed. The “MT-mimic” is shown
generically in Scheme 2. While serving the same conceptual
purpose, the analogue replaces the SꢀS reactant of the biological
system with an NꢀO moiety. Through its oxime NꢀO bond the
MT-mimic was designed to internally provide a mild S-centered
oxidation of a Cu(I) thiolate thereby converting the strongly
bonding thiolate to a weakly bonding disulfide equivalent (in this
case the SꢀN bond of the benzoisothiazole shown). This mild
oxidative trapping of thiolate was also intended to continuously
regenerate a catalytically viable “oxygenate” form of Cu(I) (and a
stoichiometric oxygenate residue to pair with ꢀB(OH)2) so that
a useful Cu(I)-catalyzed desulfitative carbonꢀcarbon bond
forming reaction with boronic acids can ensue.
’ RESULTS
The catalysis concept described above was explored through an
efficient, Cu-catalyzed desulfitative coupling of MT-mimic thiol esters
with boronic acids and organostannanes to give ketones. Since the
synthesis of ketones from thiol esters and boronic acids/organostan-
nanes is well-known,14b,a,17 the significance of the work described
here lies not in the specific synthetic demonstration, but rather in the
underlying principles of catalysis by Cu in sulfur-rich systems that are
revealed by the study. The requisite thiol ester substrates (3), which
bear an MT-mimicking sulfur pendant, were easily prepared by
standard procedures from the stable and storable O-methyl oxime
of 2-mercaptoacetophenone, 2, which, in turn, was generated from
commercially available mercaptosalicylic acid, 1, in a straightforward
fashion (Scheme 3). Although the choice of the acetophenone
derivative brings with it the issue of E/Z oxime stereoisomerism,
the structurally simpler all-E-benzaldehyde oximes were ineffective
substrates because of their tendency to eliminate MeOH and generate
the corresponding nitriles under the reaction conditions.
Exploratory studies of Cu-only catalysis using the MT-mimic 3a
were carried out (Table 1). A mixture of thiol ester 3a and either
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Scheme 3. Construction of the Metallothionein Mimic
Table 1. Control Experiments. Cu-Catalyzed Desulfitative Couplinga
a A Schlenk tube (entry 1ꢀ6) or microwave tube (entry 7ꢀ15) was equipped with a magnetic stir bar. To the tube was added the thiol ester (0.1 mmol), CuMeSal
(0.02 mmol) and organostanane (0.11 mmol) or boronic acid (0.12 mmol). After flushing with argon, anhydrous and degassed DMF (1 mL) was added. The
reaction mixture was stirred under the indicated conditions. After cooling, ethyl ether (10 mL) was added to the mixture. The reaction mixture was washedwithwater,
brine, dried over MgSO4, and evaporated. The residue was purified by preparative plate silica chromatography using hexanes/EtOAc as the eluent. b In contrast to the
analogous control experiment with the organostannane (entry 1), benzoisothiazole is not formed in this reaction. Rather, 20% of the S-arylation product (4-[2-(1-
methoxyimino-ethyl)-phenylsulfanyl]-benzaldehyde) is formed. However, when the reaction was quenched under argon prior to the work up, neither the thioether
nor the benzoisothiazole was generated. c The Z-oxime stereoisomer of the thiol ester was recovered. d The benzoisothiazole is formed in less than a one-to-one ratio
relative to the ketone because, at 60 °C, the formation of the benzoisothiazole from the intermediate Cu thiolate is slower than the rate of formation of the ketone.
Scheme 4. Control Experiments with a Simple Thiol Ester
acid were exposed to 20 mol % CuMeSal in the presence of the
external O-methyl oxime C6H5(C = NOMe)CH3 (Scheme 4). The
stannane reaction led to less than 20% of the ketone, another
transformation that appears to be stoichiometric, but not catalytic
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Table 2. Cu-Catalyzed Desulfitative Coupling Using a
Metallothionein Mimic
catalyst. Interestingly, and for reasons not currently understood,
CuII(OAc)2 was effective in promoting catalysis with the boronic
acids, but not with the organostannanes.
Two somewhat more reactive oxime variants (bearing O-carbox-
ylate and O-phenyl moieties) were also prepared and studied, but
neither system was viable for the production of ketones from thiol
esters via the copper-catalyzed chemistry. This is most likely a
function of the easy reductive cleavage of the more reactive
dNꢀO(CO)R and dNꢀOPh bonds by Cu(I),18 while the less
reactive NꢀO bond of the O-methyl oximes remains untouched by
Cu under the reaction conditions.
entry
R1
R2
ketone (%)
Boronic Acid Couplings Using 1.2 equiv of R2B(OH)2
a
Having confirmed the value of the metallothionein mimic for
catalytic turnover of Cu under anaerobic conditions, the general-
ity of this Cu-catalyzed desulfitative coupling was studied. Table 2
shows that a series of organoboron and organotin reagents are
excellent reaction partners in Cu-catalyzed couplings with dif-
ferent MT-mimic thiol esters. Near stoichiometric quantities of
either the boron or tin coupling partner suffice to generate good
to excellent yields of ketones. Electron-deficient (entries 1ꢀ6,
10, 12) and electron-rich (entries 7, 8, 13) aryl boronic acids
participated efficiently in the reaction. The coupling of an alkenyl
(entry 9) and a heteroaryl (entry 11) boronic acid was also
possible. For the boronic acid system, variation in the nature of
the acyl moiety was well accommodated: chloro, cyano, ester,
ketone, aldehyde, and phenolic functional groups were tolerated.
Loadings of Cu less than 20 mol % were acceptable in some cases,
but 20 mol % CuMeSal was suitable in all cases explored.
Organostannanes were also suitable reaction partners for a
variety of MT-mimic thiol esters. Thiol esters 3aꢀf were treated
with 1.1 equiv of an organostannane in the presence of 20 mol %
CuMeSal in DMF for 1 h under microwave heating (150 °C). As
shown in Table 2, aromatic, heteroaromatic, and aliphatic thiol
esters all coupled efficiently with a variety of electron-rich and
electron-poor aromatic and of heteroaromatic organostannanes. A
4-iodophenyl moiety (entry 16) was tolerated as was a 2-pyridyl-
stannane (entry 18).
Although the full scope and limitations of this new Cu-catalyzed
reaction are yet to be tested, the catalytic system has been extended
to include preliminary examples of aliphatic transfer from boron as
well as preliminary examples of the construction of peptidic ketones.
Early probe reactions for both systems are depicted in Figure 2.
Aliphatic boron reagents were suitable reaction partners in this
chemistry: Et3B and B-2-phenylethyl-9-BBN each reacted with thiol
ester 3a to produce the corresponding ketones in 80 and 71% yields,
respectively, and, in exploratory reactions, both a boronic acid and
an organostannane coupled with the high enantiopurity phenylala-
nine derived thiol ester 4 at 90 °C and afforded the corresponding
peptidly ketones in good yields. No racemization was observed: the
configuration of the amino acid stereogenic center was fully
preserved. Exploratory reactions with potassium alkyltrifluorobo-
rates, arylboronate esters, and arylsilanes were not successful.
1
p-tolyl
4-chlorophenyl
91
88
86
80
71
69
70
68
52
82
73
78
80
b
2
p-tolyl
4-cyanophenyl
3
p-tolyl
4-(methoxycarbonyl)phenyl
4-(formyl)phenyl
4
p-tolyl
5
p-tolyl
3-acetylphenyl
6
p-tolyl
3-formylphenyl
7
p-tolyl
3-hydroxyphenyl
8
p-tolyl
2,5-dimethoxyphenyl
trans-2-(4-chlorophenyl)vinyl
4-(methoxycarbonyl)phenyl
3-furyl
9
p-tolyl
10
11
12
13
n-propyl
CH2OAc
CH2OAc
(E)-1-propenyl
4-(methoxycarbonyl)phenyl
4-methoxyphenyl
Organostannane Couplings Using 1.1 equiv of R2SnBu3
14
15
16
17
18
19
p-tolyl
4-methoxyphenyl
4-fluoro-3-methylphenyl
4-iodophenyl
95
81
68
86
70
62
p-tolyl
p-tolyl
thienyl
n-propyl
cyclohexyl
4-methoxyphenyl
2-methoxypyridin-2-yl
4-methoxyphenyl
a Typical experimental procedure: A dry microwave tube (10 mL) was
equipped with a magnetic stir bar. To the tube was added the
corresponding thiol ester (0.1 mmol), boronic acid (0.12 mmol), and
CuMeSal (0.02 mmol). The reaction tube was flushed with argon and
sealed. Through the septum anhydrous and degassed DMF (1 mL) was
added. The mixture was subsequently heated in a microwave reactor at
150 °C for 1 h. After cooling, ethyl ether (10 mL) was added to the
mixture. The reaction mixture was washed with water (2 ꢁ 5 mL), brine
(5 mL), dried over MgSO4, and evaporated. The residue was purified by
preparative plate silica chromatography using hexanes/EtOAc as the
eluent. b Typical experimental procedure: A dry microwave tube
(10 mL) was equipped with a magnetic stir bar. To the tube were added
the corresponding thiol ester (0.1 mmol) and CuMeSal (0.02 mmol).
The reaction vessel was flushed with argon and sealed. Through the
septum the organostanane (0.11 mmol) dissolved in anhydrous and
degassed DMF (1 mL) was added. The mixture was subsequently heated
in a microwave reactor at 150 °C for 1 h. After cooling, ethyl ether
(10 mL) was added to the mixture. The reaction mixture was washed
with water, brine, dried over MgSO4, and evaporated. The residue was
purified by preparative plate silica chromatography using hexanes/
EtOAc as the eluent.
’ DISCUSSION
By way of the discrete examples presented within, the current study
establishes a conceptual framework upon which to design new
processes that are catalyzed by thiophilic metals and proceed through
metal thiolates. We suggest the general mechanism depicted in
Figure 3 for the anaerobic, Cu-catalyzed desulfitative coupling of
the “metallothionein mimic” thiol esters with boron or tin reagents.
The catalytic cycle is assumed to begin with coordination of CuI to
the thiol ester-oxime. This S,N-chelation, when followed by a
in Cu. The boronic acid again showed no evidence of reaction. The
mechanistic implications of the data presented in Table 1 and
Scheme 4 are discussed below.
Different commercially available CuIX sources including X = Cl, I,
and thiophene-2-carboxylate were all effective in this new desulfitative
cross-coupling; however, CuI-3-methylsalicylate provided the best
yields, in general. No reaction took place in the absence of a CuIX
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Figure 2. Cu-Catalyzed Desulfitative Couplings: Aliphatic Transfer Reagents and Peptidyl Ketone Synthesis.
Figure 4. Divergent behavior of boron and tin reagents exposed to
copper.
boron (or tin). However, with the designed MT-mimic, direct
reaction of the Cu-thiolate with the internal oxime functionality
effectively traps the thiolate as the benzoisothiazole and an active Cu
oxygenate catalyst is released.21 Therefore, the internal coordinating
oxime group not only lowers the barrier to reaction through
preassociation of reactants, but also serves as a metallothionein
mimic to oxidatively scavenge the thiolate and regenerate an active
metal catalyst. The thiolate scavenging motif used within this study
was modeled after the known thermal dealkylative cyclization of
2-alkylmercapto aryl oximes to benzoisothiazoles.22
Figure 3. Mimicking metallothioneins for chemical catalysis: The
proposed catalytic cycle.
The use of the acetophenone rather than a benzaldehyde oxime
moiety to trap an internal thiolate raises the question of the influence
of the oxime stereochemistry on the reaction dynamics. Although
the O-methyl oximes exist as mixtures of E and Z stereoisomers, the
stereoisomerism was not problematic, at least at the higher reaction
temperatures explored, because the oxime stereoisomers are easily
interconverted under the reaction conditions (related oxime equili-
brations in metal-catalyzed reactions are known).23 At lower reac-
tion temperatures the E-oxime was transformed cleanly to the
desired ketone and the benzoisothiazole leaving the Z-oxime
stereoisomer untouched (determined by 1H NMR analysis of the
crude reaction product prior to purification). The corresponding
2-mercaptobenzaldehyde oximes were also briefly investigated.
Although the benzaldehyde-derived oximes exist exclusively in the
transmetalation from boron or tin to CuI (transmetalation from
boron and tin to copper is an assumed essential step in a wide variety
of Cu-catalyzed bond-forming processes),11d,14,20 allows the Cu to
position the thiol ester carbonyl carbon and the organocopper R2 in
close proximity. That proximity effect along with a coordination-
induced electrophilic activation of the thiol ester can be anticipated to
lead to ketone formation through a directed reaction of the in situ
generated organocopper reagent.20
Subsequent to the carbonꢀcarbon bond forming step, a CuI-
thiolate is generated. At this point the catalytic cycle would falter in
the absence of an effective means to scavenge the thiolate from the
Cu and to regenerate a suitable “oxygenate” for pairing with the
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The mechanistic relationships among the three different Cu-
based desulfitative couplings of thioorganics with boronic acids
can be understood globally by recognition of the two key criteria
that are required for efficient catalytic turnover of Cu in a
thiophilic environment: (1) the strongly ligating thiolate must
be trapped or scavenged so that the catalytically active Cu is
liberated, free to participate in the reaction cycle, and (2) the
reaction system must be designed in order to provide the boron
reaction partner with a thermodynamically suitable replacement
moiety that will occupy the valence vacated by the “R” group that
transfers to the thioorganic.
While the O-methyloxime moiety of the current reaction system
serves to trap the thiolate and provide a full equivalent of oxygenate,
in principle, the thermodynamically strong tinꢀsulfur bond should
permit an organostannane reactant to participate in desulfitative
carbonꢀcarbon bond formation with simple thiol esters using only
catalytic quantities of Cu sources in the absence of a full equivalent
of an oxygenate fourth valence. The key to catalytic turnover of the
organostannane system with simple thiol esters will thus be
regeneration of a catalytically active CuX species through an
effective metathesis between Cu-SR0 and Bu3SnX as shown in the
Figure 5. Studies to probe this aspect of Cu-catalyzed desulfitative
transformations are currently underway.
In closing we reiterate that knowledge of the biomolecular
principles by which metals are liberated from their binding to
proteins can be used to inspire the design of effective systems for
chemical catalysis in the laboratory. In the specific case described
within, a thiophilic metal (CuI) was liberated from a strongly
binding thiolate by mimicking the mobilization of thiophilic
metals from the tightly binding tetracysteinate environment of
the metallothioneins. Additional novel and useful catalytic che-
mical discoveries may well result from further pursuits of this
concept. This new anaerobic reaction system constitutes an
alternative approach to known Cu-only catalysis in the presence
of thiolates that is based upon aerobic Cu-thiolate chemistry.13
Figure 5. Organostannane desulfitative coupling with Cu only: A
catalytic cycle.
E-configuration, their effectiveness in the designed reaction system
was compromised by their competitive elimination to aryl cyanides.
Figure 4 provides an explanation for the different behavior of the
boron and tin reagents in their control experiment reactions with the
simple thiol ester p-tolyl(CO)S-p-tolyl. Only the tin reagent, (4-
methoxyphenyl)tri-n-butylstannane, generates the corresponding ke-
tone from the simple thiol ester in a reaction that is stoichiometric in
Cu. The boronic acid, 4-(formylphenyl) boronic acid, returns the
thiol ester untouched. Support for a rapid Cu-mediated proto-
deborylation of the boronic acid in the absence of a suitable
coordinating thiol ester reactant as suggested in Figure 4 is found
in earlier studies of boronic acid-based desulfitative transformations.16i
The control experiments suggest that the organocopper intermediate
generated from the organostannane reaction variant, which lacks the
active OH residues of the boronic acid, possesses a sufficient lifetime
to allow reaction with the simple thiol ester.
’ CONCLUSIONS
To date three fundamentally different metal-mediated methods
have been developed for the pH-neutral desulfitative reaction of
boronic acids and organostannanes with thioorganic substrates. The
original “1st-generation process” takes place under anaerobic condi-
tions and requires a palladium catalyst partnered with a stoichiometric
quantity of a Cu(I) carboxylate cofactor.6a,13 The thioorganic reactant
spans a variety of sp2 and sp systems; organostannanes also function
as suitable reaction partners. In pursuing similar transformations that
would require only catalytic quantities of the Cu(I) carboxylate, a
“2nd-generation” pH-neutral, desulfitative coupling of boronic acids
with thiol esters was developed. This reaction system takes place
aerobically and requires only catalytic quantities of Cu.13 The aerobic
second generation desulfitative reaction therefore circumvents two
limitations of the first generation family of reactions: it requires no Pd
and it turns over using only catalytic quantities of Cu. However, this
mechanistically different aerobic reaction system (which currently is
limited to thiol ester reactants) imposes a new limitation by requiring
a second, sacrificial equivalent of the boronic acid in order to complete
the catalytic cycle.
’ METHODS
Preparation of 1-(2-Mercaptophenyl)ethanone O-Methylox-
ime(2).To a dry and argon-flushed 100 mL round-bottomed flask equipped
with a magnetic stirring bar was added 20-mercaptoacetophenone24 (3.04 g,
20 mmol), O-methylhydroxylamine hydrochloride (2.51 g, 30 mmol), and
MeOH (60 mL). Pyridine (2.77 g, 35 mmol) was then slowly added via
syringe. After the reaction mixture was stirred at room temperature overnight,
the solvent was evaporated. The residue was dissolved in diethyl ether
(20 mL), and the organic phase was washed with 1 M aqueous HCl (2 ꢁ
10 mL), water (10 mL), and brine (5 mL). After the mixture was dried over
anhydrous MgSO4 and filtered, the solvent was evaporated. The product was
purified by flash chromatography (silica gel, 20:1 hexanes/EtOAc) to afford
the title compound as a yellow oil (6:1 E/Z mixture of isomers, 3.11 g, 86%).
Major isomer: 1H NMR (400 MHz, CDCl3) δ 7.32ꢀ7.27 (m, 2H),
7.16ꢀ7.14 (m, 2H), 4.01 (s, 3H), 3.97 (s, 1H), 2.22 (s, 3H). Characteristic
1
signals for minor isomer: H NMR δ 3.84 (s, 3H), 2.16 (s, 3H). Major
isomer: 13C NMR (100 MHz, CDCl3) δ 155.8, 135.8, 131.2, 129.2, 128.9,
125.7, 62.2, 15.3. IR (neat, cmꢀ1): 3061 (m), 2937 (s), 2548 (m), 1613 (m).
HRMS (FAB) calcd for C9H12ONS (MþHþ): 182.0634; found, 182.0632.
Preparation of S-2-(1-(Methoxyimino)ethyl)phenyl 4-Methyl-
benzothioate (3a). The preparation of 3a is representative for the
synthesis of the other thiol esters 3bꢀf. To a dry and argon-flushed 50 mL
round-bottomed flask equipped with a magnetic stirring bar was added 1-(2-
mercaptophenyl)ethanone O-methyloxime (2) (181 mg, 1.0 mmol), p-
toluoyl chloride (162 mg, 1.05 mmol) and THF (20 mL). Pyridine (87 mg,
1.1 mmol) was added slowly via syringe, and after the mixture was stirred at
The chemistry described within this paper demonstrates an
alternative and mechanistically unique desulfitative reaction
system that is catalyzed by Cu-only. It was designed to be
catalytic in Cu and proceed at neutral pH like the aerobic second
generation reaction system, but, in contrast, it uses a single
equivalent of the boronic acid or organostannanes reaction
partner and functions anaerobically, not aerobically.
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room temperature for 4 h, the white precipitate was removed by filtration. The
filtrate was washed with water (2ꢁ 10 mL) and brine (5 mL) and then dried
over anhydrous MgSO4. The solvent was evaporated to give a yellow oil that
was purified by flash chromatography (silica gel, 10:1 hexanes/EtOAc) to
afford the title compound as a clear oil (6:1 mixture of E/Z isomers, 293 mg,
98%). Characterization details are provided in the Supporting Information.
Microwave Irradiation Experiments. Microwave irradiation
experiments were carried out using a Discover microwave reactor from
CEM Corporation. All experiments were performed in sealed tubes
(capacity 10 mL) under an argon atmosphere utilizing microwave
irradiation of 300 W. The temperature was ramped from room
temperature to 150 °C in 1 min. Once this temperature was reached,
the reaction mixture was held at 150 °C for 60 min.
Sci.U.S.A. 1998, 95, 3489–3494. (f) Maret, W. Proc. Natl. Acad. Sci. U.S.A.
1994, 91, 237–241.
(4) Song, C. Catal. Today 2003, 86, 211–263.
(5) Smith, B. M. Chem. Soc. Rev. 2008, 37, 470–478.
(6) (a) Prokopcovꢀa, H.; Kappe, O. C. Angew. Chem., Int. Ed. 2009,
48, 2276–2286. (b) Dubbaka, S. R.; Vogel, P. Angew. Chem., Int. Ed.
2005, 44, 7674–7684.
(7) Coyle, P.; Philcoxa, J. C.; Carey, L. C.; Rofea, A. M. Cell. Mol. Life
Sci. 2002, 59, 627–647.
(8) Maret, W.; Vallee, B. L. Proc. Natl. Acad. Sci. U.S.A. 1998,
95, 3478–3482.
(9) Maret, W. Neurochem. Int. 1995, 27, 111–117.
€
(10) Zangger, K.; Oz, G.; Haslinger, E.; Kunert, O.; Armitage, I. M.
FASEB 2001, 15, 1303–1305.
Representative Procedure for Cu-Catalyzed Desulfitative
Couplings. To a dry microwave tube (10 mL) equipped with a stirring
bar was added S-2-(1-(methoxyimino)ethyl)phenyl 4-methylbenzothio-
ate (3a) (30 mg, 0.1 mmol), 4-chlorophenyl boronic acid (19 mg, 0.12
mmol), and CuMeSal (4 mg, 0.02 mmol). The reaction tube was flushed
with argon and sealed with a septum. Anhydrous and degassed DMF
(1 mL) was added, and the mixture was subsequently heated in a
microwave reactor at 150 °C for 1 h. After it was cooled, the reaction
mixture was diluted with diethyl ether (10 mL). The reaction mixture
was washed with water (2 ꢁ 5 mL) and brine (3 mL) and dried over
anhydrous MgSO4. The solvent was removed at reduced pressure, and
the crude product was purified by preparative plate silica gel chroma-
tography using hexanes/EtOAc (4:1) as the eluent. 4-Chloro-40-methyl-
benzophenone was obtained as a white solid (21 mg, 91%).
Characterization details are provided in the Supporting Information.
(11) (a) Phipps, R. J.; Gaunt, M. J. Science (Washington, D.C.) 2009,
323, 1593–1597. (b) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev.
2008, 108, 3054–3131. (c) Alexakis, A.; B€ackvall, J. E.; Krause, N.;
Pꢁamies, O.; Diꢀeuez, M. Chem. Rev. 2008, 108, 2796–2823. (d) Beletskaya,
I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337–2364. (e) Ley,
S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–5449.
(12) Musaev, D. G.; Liebeskind, L. S. Organometallics 2009,
28, 4639–4642.
(13) (a) Villalobos, J. M.; Srogl, J.; Liebeskind, L. S. J. Am. Chem. Soc.
2007, 129, 15734–15735. (b) Liebeskind, L. S.; Yang, H.; Li, H. Angew.
Chem., Int. Ed. 2009, 48, 1417–1421.
(14) (a) Li, H.; Yang, H.; Liebeskind, L. S. Org. Lett. 2008,
10, 4375–4378. (b) Egi, M.; Liebeskind, L. S. Org. Lett. 2003,
5, 801–802. (c) Alphonse, F.-A.; Suzenet, F.; Keromnes, A.; Lebret,
B.; Guillaumet, G. Org. Lett. 2003, 5, 803–805.
(15) Sigel, H.; Scheller, K. H.; Rheinberger, V. M.; Fischer, B. E.
J. Chem. Soc., Dalton Trans. 1980, 1022–1028.
(16) (a) Liebeskind, L. S.; Yang, H.; Li, H. Angew. Chem., Int. Ed.
2009, 48, 1417–1421. (b) Yang, H.; Liebeskind, L. S. Org. Lett. 2007,
9, 2993–2995. (c) Yang, H.; Li, H.; Wittenberg, R.; Egi, M.; Huang, W.;
Liebeskind, L. S. J. Am. Chem. Soc. 2007, 129, 1132–1140. (d)
Rodríguez-Cendejas, C. G.; Liebeskind, L. S.; Pe~na-Cabrera, E. ARKI-
VOC 2005, 6, 250–256. (e) Fausett, B. W.; Liebeskind, L. S. J. Org. Chem.
2005, 70, 4851–4853. (f) Yu, Y.; Liebeskind, L. S. J. Org. Chem. 2004,
69, 3554–3557. (g) Wittenberg, R.; Srogl, J.; Egi, M.; Liebeskind, L. S.
Org. Lett. 2003, 5, 3033–3035. (h) Savarin, C.; Srogl, J.; Liebeskind, L. S.
Org. Lett. 2000, 2, 3229–3331. (i) Liebeskind, L. S.; Srogl, J. J. Am. Chem.
Soc. 2000, 122, 11260–11261.
(17) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2001, 3, 91–93.
(18) Liu, S.; Yu, Y.; Liebeskind, L. S. Org. Lett. 2007, 9, 1947–1950.
(19) (a) Falck, J. R.; Bhatt, R. K.; Ye, J. J. Am. Chem. Soc. 1995,
117, 5973–5982. (b) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc.
1996, 118, 2748–2749. (c) Chan, D. M. T.; Lam, P. Y. S. In Boronic Acids
- Preparation, Applications in Organic Synthesis and Medicine; Hall, D. G.,
Ed.; Wiley-VCH: Weinheim, Germany, 2005, p 205ꢀ240; (d) Falck,
J. R.; Patel, P. K.; Bandyopadhyay, A. J. Am. Chem. Soc. 2007,
129, 790–793.
(20) Breit, B.; Schmidt, Y. Chem. Rev. 2008, 108, 2928–2951.
(21) As a control experiment, the 2-mercaptoacetophenone O-
methyloxime was treated with 1 equiv of Cu(I) 3-methylsalicylate in
dry, degassed EtOAc under argon. The resulting yellow precipitate was
filtered and dried under vacuum. This yellow solid was placed in a flame-
dried test tube with dry, degassed DMF under argon and monitored by
TLC for formation of the benzoisothiazole. No product was observed
after 2 h at room temperature nor after 2 h at 40 °C. After 2 h at 60 °C a
trace of product was noted. The reaction was then warmed to 80 °C
where product formation ensued. After 24 h at 80 °C the reaction
mixture was diluted with water and extracted into diethyl ether, and the
product residue was purified by preparative silica gel chromatography.
The benzoisothiazole was isolated in 81% yield.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures,
b
synthesis, and characterization of all new compounds and
scanned spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
lanny.liebeskind@emory.edu
Present Addresses
†Department of Chemistry, University of Chicago, 5735 South
Ellis Avenue, Chicago, IL 60637.
’ ACKNOWLEDGMENT
The National Institutes of General Medical Sciences, DHHS,
supported this investigation through Grant No. GM066153. G.
Allred of Synthonix provided the boronic acids, organostan-
nanes, and Cu salts used in our studies. E. Garnier-Amblard and
H. Li provided critical proofreading and suggestions.
’ REFERENCES
(1) (a) Waldron, K. J.; Robinson, N. J. Nat. Rev. 2009, 6, 25–35. (b)
Tottey, S.; Harvie, D., R.; Robinson, N. J. Acc. Chem. Res. 2005,
38, 775–783.
(2) Huffman, D. L.; O’Halloran, T. V. Annu. Rev. Biochem. 2001,
70, 677–701.
(3) (a) Maret, W. Biochemistry 2004, 43, 3301–3309. (b) Chen, Y.;
Irie, Y.; Keung, W. M.; Maret, W. Biochemistry 2002, 41, 8360–8367. (c)
Hartmann, H. J.; Weser, U. BioMetals 2000, 13, 153–156. (d) Jacob, C.;
Maret, W.; Vallee, B. L. Biochem. Biophys. Res. Commun. 1998,
248, 569–573. (e) Jacob, C.; Maret, W.; Vallee, B. L. Proc. Natl. Acad.
(22) (a) Crawford, R. J.; Woo, C. J. Org. Chem. 1966, 31, 1655–1656.
(b) Meth-Cohn, O.; Tarnowski, B. Synthesis 1978, 58–60. (c) Lawson,
A. J. Phosphorus, Sulfur Silicon Relat. Elem. 1982, 12, 357–367. (d)
McKinnon, D. M.; Kingsley, R. L. Can. J. Chem. 1988, 66, 1405–1409.
6409
dx.doi.org/10.1021/ja200792m |J. Am. Chem. Soc. 2011, 133, 6403–6410

Journal of the American Chemical Society
ARTICLE
(e) K€anel, H.-R.; Wegmann, A.; Neff, D. U.S. Patent 5,527,917, 1996.
(f) Kagano, H.; Goda, H.; Yamamoto, M.; Sakaue, S.; Toudou, M. U.S.
Patent 5,856,504, 1999.
(23) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004,
126, 9542–9543.
(24) Topolski, M. J. Org. Chem. 1995, 60, 5588–5594.
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dx.doi.org/10.1021/ja200792m |J. Am. Chem. Soc. 2011, 133, 6403–6410