A new paradigm for carbon-carbon bond formation: Aerobic, copper-templated cross-coupling

Article abstract of DOI:10.1021/ja074931n

Thiol esters and boronic acids react to produce ketones under aerobic conditions in the presence of catalytic quantities of a Cu^I or Cu^II salt. The reaction occurs at reasonable rates between room temperature and 50 °C at neutral pH using thiol esters derived from bulky 2° amides of thiosalicylamides such as those based on N-tert-butyl-2-mercaptobenzamide. In this mechanistically unprecedented reaction system, the carbon-carbon bond formation occurs through templating of the thiol ester and the boronic acid at copper; the system is rendered catalytic in copper under the aerobic conditions. Copyright

Full text of DOI:10.1021/ja074931n

Published on Web 11/30/2007
A New Paradigm for Carbon-Carbon Bond Formation: Aerobic,
Copper-Templated Cross-Coupling
Janette M. Villalobos, Jiri Srogl,† and Lanny S. Liebeskind*
Department of Chemistry, Emory UniVersity, 1515 Dickey DriVe, Atlanta, Georgia 30322
Received July 4, 2007; E-mail: lanny.liebeskind@emory.edu
Table 1. S-Pendant Effects in Cu-Catalyzed Aerobic Coupling
We describe herein a mechanistically unprecedented system for
the construction of carbon-carbon bonds: the copper-templated
coupling of a thioorganic and a boronic acid that is rendered
catalytic under aerobic conditions. This new reaction type evolved
from mechanistically distinct earlier transformations discovered in
this laboratory1-3 and subsequently extended in others:4-9 the
anaerobic coupling of a wide range of thioorganics with either
boronic acids or organostannanes that require the presence of
catalytic quantities of a palladium source and stoichiometric
quantities of a CuI carboxylate. In this communication, we reveal
the unique attributes of the copper-catalyzed, aerobic reaction
system applied to the formation of ketones by the coupling of thiol
esters with boronic acids at neutral pH.
ketone
(%)
thioether
(%)
biaryla
(%)
entry
pendant
1
2
3
4
5
6
7
8
-C6H5
trace
6
trace
34
30
32
trace
trace
trace
28b
57
37
31
trace
54
trace
7
4
-(2-C6H4NHCOPh)
-(CH2)2CONHt-Bu
-(2-C6H4CONHPh)
-(2-C6H4CONmorpholinyl)
-(2-C6H4CONHMe)
-(2-C6H4CONHi-Pr)
-(2-C6H4CONHt-Bu)
25b
33b
77
81
84
75
All published thioorganic-boronic acid cross-couplings have
required catalytic quantities of Pd and at least a stoichiometric
quantity of a CuI carboxylate (or diphenylphosphinate) as a reaction
mediator. Simple balancing of the generic reaction equation reveals
the reasons for the latter requirement. The CuI ion pairs with the
thiolate in a thermodynamically strong Cu-SR bond, while a full
equivalent of the borophilic carboxylate counterion drives the
-B(OH)2 moiety to its thermodynamic sink, R′C(O)OB(OH)2. This
implies that the reaction system could be rendered catalytic in Cu
if a Cu oxygenate could be regenerated from Cu-SR.10 We
hypothesized that thioorganic-boronic acid cross-couplings carried
out under aerobic conditions in the presence of a second sacrificial
equivalent of the boronic acid would achieve the desired goal. The
strong Cu-SR bond would be broken by forming a thioether (using
the second equivalent of boronic acid11), and a Cu oxygenate (of
undefined oxidation state) would be released to the system.
To test this hypothesis, thiol esters possessing a variety of
S-pendants were constructed and treated, open to air, with p-
methoxyphenylboronic acid in DMF in the presence of catalytic
CuI-3-methylsalicylate and, in the initial studies, with cocatalytic
Pd sources. Control experiments revealed that a palladium co-
catalyst was not required under the aerobic reaction conditions,
making this system mechanistically distinct from our earlier
thioorganic-boronic acid couplings. As shown in Table 1, only
those thiol esters possessing appropriately positioned ligating
S-pendant groups participated in efficient aerobic coupling with
boronic acids. Key observations included (1) the requirement for a
ligating functional group positioned ortho but not para to the
S-pendant linkage, (2) the optimum performance of thiol esters
derived from bulky -NHi-Pr and -NHt-Bu thiosalicylamides
(contrast entries 5 and 6 with 7 and 8, Table 1), and (3) the
formation of the S-arylated pendant in a roughly 1:1 ratio with the
desired ketonic product.
a Biaryl ) 4,4′-dimethoxybiphenyl, boronic acid homocoupling. b Isolated
as a mixture with coeluting starting material; yield estimated from 1H NMR
using 4,4′-di-tert-butylbiphenyl as an internal standard.
Table 2. Aerobic Coupling of Thiol Esters and Boronic Acids
ketone
(%)
thioether
(%)
entry
R1
R2
1
2
3
4
5
phenyl
phenyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
methyl
n-propyl
ω-decynyl
(E)-propenyl
p-(MeO)C6H4
furan-2-carbaldehyde-5-yl
2-BrC6H4
2-naphthyl
(E)-â-styryl
(E)-1-pentadecenyl
3,4-methylenedioxyphenyl
6-methoxypyridin-3-yl
2-thienyl
81
91
86
83
87
97
75
68
50
74
75
78
83
92
83
74
71
61
51
81
6a-c
7
8
9
10c
2-furyl
a Propylene oxide was added as a mild acid scavenger to minimize
protodeborylation. b CuI-2,6-dihydroxycarboxylate was used, giving slightly
better yields than CuI-3-methylsalicylate. c Yield is based on recovered
starting material.
with 2.5 equiv of a boronic acid and 5 mol% CuI-3-methylsalicylate
in DMF at 50 °C open to air. This study, depicted in Table 2,
demonstrates that aromatic, heteroaromatic, and alkenyl boronic
acids are suitable reaction partners for aromatic, aliphatic, and R,â-
unsaturated thiol esters. Aldehydic and acetylenic functional groups
are tolerated (entries 2 and 9) as is modest steric hindrance in the
boronic acid (entry 3). Cyclohexylboronic acid, the only aliphatic
boronic acid explored in this study, was unreactive.
Control experiments with stoichiometric copper sources under
argon suggest the importance of Cu oxidation states >1 in the
specific carbon-carbon bond forming step of the overall process:
under identical conditions, CuI-3-methylsalicylate produced less than
The scope of this new aerobic cross-coupling was briefly probed
through the reaction of a variety of S-acyl-NHt-Bu thiosalicylamides
† Current address: Academy of Sciences of the Czech Republic, Institute of
Organic Chemistry and Biochemistry, Flemingovo nam. 2, 166 10 Prague, Czech
Republic.
9
15734
J. AM. CHEM. SOC. 2007, 129, 15734-15735
10.1021/ja074931n CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
by reaction of the CuII/III thiolate with the second (sacrificial)
equivalent of the boronic acid.11,18 This would regenerate the
requisite CuI for reentry into the catalytic cycle and remove thiolate
ligand from the reaction system by producing the weakly coordinat-
ing S-arylation product. Apparently, binding of the chelating thiol
ester to the Cu catalyst significantly modulates its ability to induce
undesired side reactions such as Cu-catalyzed aerobic homocoupling
of the boronic acid19 and Castro-Stevens-like oxidative dimeriza-
tion of the terminal alkyne shown in entry 9 of Table 2.
Scheme 1. Proposed Mechanism
In its current manifestation, this new aerobic coupling of thiol
esters and boronic acids should find utility in applications where
highly selective functionalizations of complex molecules are
required and where the need for a second equivalent of boronic
acid and formation of the thioether side product are both unim-
portant. This will be demonstrated in the near future through
disclosure of the selective carbon-carbon bond functionalization
of small peptides with boronic acids using catalytic Cu under
ambient, aerobic conditions.20
20% of the ketone, while CuII(OAc)2 generated the ketone in 60%
yield. In contrast to CuII(OAc)2, stoichiometric CuIICl2 was
completely ineffective in promoting the ketone synthesis under
argon, further attesting to the importance of partnering an oxygenate
counterion with the -B(OH)2 moiety in this coupling. Significantly,
using catalytic quantities of Cu open to air, all CuIX sources
explored were effective, regardless of the nature of the counterion
(X ) halide, carboxylate, diphenylphosphinate), but only those
CuIIX2 sources bearing an oxygenate counterion (X ) carboxylate
or diphenylphosphinate, but not halide) were able to initiate and
support the aerobic reaction. We propose that CuI must be accessible
for effective catalysis. This requires in situ reduction of a CuII pre-
catalyst to CuI by the boronic acid, an apparently facile process
with an oxygenate but not with a chloride counterion on CuII. This
is reminiscent of the requirement for an oxygenate counterion to
facilitate boron to palladium transmetalation in Miyaura-Suzuki
cross-couplings.12
Acknowledgment. The National Institutes of General Medical
Sciences, DHHS, supported this investigation through Grant No.
GM066153. We thank Dr. Paul Reider of Amgen for his interest
in and support of our work. Dr. Gary Allred of Synthonix provided
the boronic acids and Cu salts used in our studies. We thank our
colleague Dr. Jamal Musaev for very stimulating and insightful
conversations. J.M.V. thanks the ARCS Foundation for a graduate
fellowship.
Supporting Information Available: Experimental procedures,
synthesis and characterization of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
The mechanism of this aerobic cross-coupling must take into
account (1) active catalysis without Pd, using sources of Cu only,
(2) catalytic turnover under aerobic but not anaerobic conditions,
(3) the apparent requirement for accessing CuI during the catalytic
cycle, (4) the requirement for a thiol ester bearing a chelating
S-pendant, and finally (5) the production in a roughly 1:1 ratio of
both the desired ketone and the thioether derived from the S-pendant
and the boronic acid. The absence of palladium in the catalytic
sequence and the lack of any precedent for oxidative addition of
thiol esters to CuI make a traditional oxidative addition-trans-
metalation-reductive elimination pathway for this new reaction
unlikely. Rather, on the basis of the control experiments, we suggest
that the thiol ester-boronic acid aerobic cross-coupling occurs
through a novel, higher oxidation state, Cu-templated coupling
reaction (Scheme 1).
Closely paralleling extensively documented studies of CuI-
dioxygen reactions,13-17 we suggest that the process is initiated by
aerobic activation of CuI coordinated to the thiol ester (stage 1),
which generates a higher oxidation state CuII/III intermediate (both
CuII and CuIII are accessible through the low-energy interconversion
of [Cu2(µ-η2:η2-O2]2+ and [Cu2(µ-O2]2+).13-17 Metal templating by
CuII/III provides simultaneous Lewis acid activation of the thiol ester
along with templated delivery of an adjacent nucleophilic organo-
metallic moiety (R2 in Scheme 1, delivered directly either from
boron or through the intermediacy of Cu) producing the ketone
and a higher oxidation Cu-thiolate. The catalytic cycle is completed
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