Desulfitative carbon-carbon cross-coupling of thioamide fragments with boronic acids

Article abstract of DOI:10.1002/adsc.200600566

A novel and general carbon-carbon cross-coupling reaction between cyclic thioamides and boronic acids is described. The reaction is catalytic in palladium(O) and requires stoichiometric amounts of a copper(I) carboxylate as metal cofactor. The mode of cross-coupling in the reaction of cyclic thioamides with boronic acids is easily tunable between carbon-carbon and carbon-sulfur cross-coupling. While the catalytic palladium(O)/ copper(I) system provides carbon-carbon bond formation with extrusion of sulfur, stoichiometric quantities of copper(II) under air mediate carbon-sulfur bond formation.

Full text of DOI:10.1002/adsc.200600566

UPDATES
DOI: 10.1002/adsc.200600566
Desulfitative Carbon–Carbon Cross-Coupling of Thioamide
Fragments with Boronic Acids
a
a,
Hana Prokopcovµ and C. Oliver Kappe *
a
Christian Doppler Laboratory for Microwave Chemistry (CDLMC) and Institute of Chemistry, Karl-Franzens University
Graz, Heinrichstrasse 28, 8010 Graz, Austria
Phone: (+43)-316-380-5352; fax: (+43)-316-380-9840; e-mail: oliver.kappe@uni-graz.at
Received: September 17, 2006; Published online: January 8, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
[
4]
[5]
[6]
Abstract: A novel and general carbon–carbon
cross-coupling reaction between cyclic thioamides
and boronic acids is described. The reaction is cata-
lytic in palladium(0) and requires stoichiometric
amounts of a copper(I) carboxylate as metal cofac-
tor. The mode of cross-coupling in the reaction of
cyclic thioamides with boronic acids is easily tuna-
ble between carbon–carbon and carbon–sulfur
cross-coupling. While the catalytic palladium(0)/
copper(I) systemprovides carbon–carbon bond for-
mation with extrusion of sulfur, stoichiometric
quantities of copper(II) under air mediate carbon–
sulfur bond formation.
ed. Notably, sulfonyl chlorides, sulfones, sulfoni-
[7] [8] [9]
umsalts,
thioalkynes, thiol esters and thioeth-
have all been shown to undergo efficient Pd-
[
10,11]
ers
catalyzed desulfitative cross-couplings with boronic
acids leading to the formation of a new carbon-
carbon bond with concomitant extrusion of sulfur.
[4–11]
[11]
In our laboratories we have recently discovered
an unprecedented direct Pd-catalyzed, Cu(I)-mediat-
ed carbon–carbon cross-coupling of a cyclic thiourea
with a boronic acid under non-basic Liebeskind–
[
7–10,12]
Srogl
reaction conditions. The observed transi-
tion metal-catalyzed desulfitative carbon–carbon cou-
pling of a thiourea containing a latent free thiol func-
tionality can be considered as highly unusual, since
here the competing carbon–sulfur cross-coupling is
[
13]
Keywords: copper; cross-coupling; homogeneous
catalysis; microwave heating; palladium; thio-
amides
[
11,14–17]
typically the preferred pathway.
Because of the
potential synthetic utility and interesting mechanistic
implications of this novel carbon–carbon cross-cou-
pling reaction we became interested in the scope and
limitations of this synthetic transformation and now
report the development of a general synthetic method
Transition metal-catalyzed carbon–carbon and for the coupling of cyclic thioamide fragments with
carbon–heteroatomcross-coupling reactions belong to
the most powerful and flexible transformations
boronic acids under nonbasic reaction conditions.
As a model system for our optimization studies we
known to organic chemists and have revolutionized first investigated the potential for Pd-catalyzed,
the art and practice of synthesis in the last two de- Cu(I)-mediated carbon–carbon cross-coupling be-
[1]
cades. Among the plethora of cross-coupling proce- tween pyridine-2(1H)-thione and phenylboronic acid
dures known today, protocols involving boronic acids (Table 1, entry 1). Building on our previous experi-
[
11]
as coupling partners are becoming increasingly popu- ence,
the reaction conditions were refined using
[2]
lar. The facts that most boronic acids are air- and controlled microwave heating (MW) in sealed ves-
[
18]
moisture-stable, of relatively low toxicity, and are sels. One of the best sets of conditions for coupling
nowadays commercially available, make cross-cou- of the pyridine-2(1H)-thione substrate utilized 1.2
pling chemistry utilizing these reagents highly attrac- equivs. of phenylboronic acid, 4.0 mol% [Pd
A
H
R
U
G
tive. as a catalyst, and 3.0 equivs. of Cu(I) thiophene-2-car-
[
10]
One of the most valuable transformations in this boxylate (CuTC) as a metal cofactor in dry THF.
context arguably is the Pd-catalyzed Suzuki–Miyaura An inert atmosphere, preventing oxidation of the
biaryl cross-coupling involving aryl halides and boron- Cu(I) cofactor to a Cu(II) species is also advanta-
[
1,3]
ic acids as coupling partners.
In addition to aryl geous in order to achieve high product yields. The
halides, the use of organosulfur compounds as electro- cleanest conversions were achieved by exposing the
philic reaction partners has recently also been report- heterogeneous reaction mixture to microwave heating
448
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 448 – 452

Desulfitative Carbon–Carbon Cross-Coupling of Thioamide Fragments
UPDATES
Table 1. Pd(0)-catalyzed, Cu(I)-mediated carbon–carbon to incomplete conversions. In order to further im-
cross-coupling of cyclic thioamide fragments with phenylbor-
onic acid.
prove the product yield in this coupling process an ad-
[a]
ditional quantity of the Pd catalyst (4 mol%) was
added to the reaction mixture after the first heating
cycle. The vessel was subsequently resubjected to mi-
crowave heating at 1008C for an additional hour. The
application of this two-step procedure ultimately led
to a 90% isolated yield of the 2-phenylpyridine cou-
pling product after column chromatography. Careful
monitoring of the crude reaction mixture demonstrat-
[
b]
Entry
1
Substrate
Product
Yield [%] ed that the coupling was completely selective for the
carbon–carbon pathway, and that no carbon–sulfur
[
c]
cross-coupling product (see below) was observed.
We were indeed pleased to find that pyridine-
90 (71)
2(1H)-thione did undergo the anticipated carbon–
carbon cross-coupling with phenylboronic acid in high
yield, which indicated that these desulfitative cou-
2
3
83
[
11]
plings are not restricted to cyclic thioureas but are
also possible with thioamide fragments embedded
into an aromatic heterocycle. In order to investigate
the scope of this transformation we selected a small
but diverse set of heterocycles containing thioamide
fragments and performed cross-couplings with phenyl-
boronic acid applying our optimized set of conditions.
As can be seen fromthe data presented in Table 1,
successful cross-coupling was achieved with a variety
of aromatic and non-aromatic six-membered and five-
membered heterocycles containing thioamide frag-
ments. In general, good to high product yields were
obtained using the standard reaction conditions speci-
fied above. The only exception proved to be 1,3-dihy-
droimidazole-2-thione (entry 9) which provided 2-
phenyl-1H-imidazole in a very modest 8% yield. The
success of the Pd-catalyzed, Cu(I)-mediated carbon–
carbon cross-coupling is apparently independent on
the ring size, aromaticity/non-aromaticity, the pres-
ence of additional heteroatoms or other functional
87
97
4
5
6
96
75
7
52
[
19]
groups (Table 1, entries 1–10). However, the struc-
tural integrity of the thioamide motif needs to be pre-
served for an efficient carbon–carbon cross-coupling.
Thus, attempted cross-coupling of 4-pyridinethiol with
phenylboronic acid produced only 15% of the cross-
coupled product, whereas the isomeric 2-pyridinethiol
8
9
93
8
(
entry 1) provided a 90% yield under identical reac-
tion conditions. Attempted coupling of simple aro-
matic thiols (e.g., p-methylthiophenol) with phenyl-
boronic acid using the Pd(0)-catalyzed, Cu(I)-mediat-
ed protocol led to no detectable carbon–carbon cross-
coupling products.
1
0
67
[
[
[
a]
For a general procedure, see the Experimental Section.
Isolated yields after column chromatography.
Yield after 1 h.
b]
c]
The mechanism of this desulfitative cross-coupling
involving cyclic thioamides is related to the traditional
[
7–12]
Liebeskind–Srogl protocols,
in particular to the
cross-coupling of N-heteroaromatic thioethers with
[
10]
at 1008C for 1 h, leading to a 71% isolated yield of boronic acids. The reaction requires both the Pd(0)
the anticipated 2-phenylpyridine product. Higher re- catalyst and the specific Cu(I) carboxylate additive
action temperatures did not improve the efficiency of (CuTC) in stoichiometric quantities. Carbon–carbon
this transformation, while shorter reaction times led coupling products were not obtained when CuTC was
Adv. Synth. Catal. 2007, 349, 448 – 452
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
449

Hana Prokopcovµ and C. Oliver Kappe
UPDATES
Figure 1. Proposed mechanism for the Pd(0)-catalyzed,
Cu(I)-mediated carbon–carbon cross-coupling of thioamides
and boronic acids. 2-T=2-thienyl. TC=thiophene-2-carbox-
ylate.
Scheme 1. Orthogonal reactivity between carbon–carbon,
carbon–sulfur and Suzuki–Miyaura biaryl cross-couplings in
replaced with other Cu(I) salts such as CuBr or CuCl.
The unique requirement of a Cu(I) carboxylate such
as CuTC is accommodated by the intermediate D
shown in Figure 1: the Cu(I) carboxylate simultane-
5
-bromopyridine-2(1H)-thione.
ously polarizes the PdÀS bond through Cu(I) coordi- substrate. In addition to a thioamide fragment, this or-
nation to S while activating the trivalent boron ganosulfur compound also contained a Suzuki-active
[
7–12]
through coordination of the carboxylate to B.
In the case of thioamides, however, we experienced ed
that 2–3 equivs. of the CuTC cofactor needed to be carbon–sulfur cross-couplings to the base-catalyzed
bromide which allowed us to evaluate the anticipat-
[
22]
orthogonality of both the carbon–carbon and
[
3]
employed in order to achieve high conversions. We Suzuki–Miyaura biaryl coupling.
therefore propose the initial formation of a Cu(I) thi-
Using our optimized conditions for Pd-catalyzed
[
20]
olate species of type A
which then can undergo desulfitative carbon–carbon cross-coupling (Table 1),
[
21]
either oxidative addition to the Pd(0) catalyst (B) 5-bromopyridine-2(1H)-thione (1) was readily con-
or further complexation with an additional equivalent verted into 5-bromo-2-phenylpyridine (2) by treat-
of the CuTC cofactor (C). Both pathways will ulti- ment with phenylboronic acid in 87% yield
mately lead to the key intermediate D which subse- (Scheme 1). There was no evidence for a competing
quently undergoes baseless transmetalation with ex- Suzuki–Miyaura cross-coupling at the bromide posi-
trusion of Cu S followed by reductive elimination in tion. For the Pd(0)/Cu(I) coupling pathway, this
2
order to provide the carbon–carbon cross-coupled unique selectivity is due to the use of CuTC as a
products.
A unique advantage of using thioamides as starting alyst and by the neutral reaction conditions.
materials for desulfitative carbon-carbon cross-cou- To gain a mechanistic insight into the alternative
metal cofactor of higher thiophilicity than the Pd cat-
[
22]
pling reactions is the fact that the presence of the transition metal-mediated carbon–sulfur cross-cou-
latent thiol functionality will also allow carbon-sulfur pling pathway we have also performed the cross-cou-
bond formation under suitable reaction conditions. pling of 1 with phenylboronic acid (4.0 equivs.) using
For cyclic thioamides, Cu-mediated carbon–sulfur stoichiometric quantities of Cu
A
H
R
U
G
cross-coupling reactions with boronic acids have been with 1,10-phenanthroline as a ligand. The expected
[
11,15]
described,
although the mechanism for these Cu- carbon–sulfur cross-coupling product 3 was obtained
[16]
mediated transformations is still under debate.
in 71% yield following a protocol that involved initial
In order to explore the suitability of cyclic thio- in situ roomtemperature oxidation of the thiol to its
amides for carbon–sulfur bond formation we have se- disulfide promoted by Cu(II) and air, followed by mi-
lected 5-bromopyridine-2(1H)-thione (1) as a model crowave heating to 1108C for 2 h. Careful HPLC
450
www.asc.wiley-vch.de
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 448 – 452

Desulfitative Carbon–Carbon Cross-Coupling of Thioamide Fragments
UPDATES
monitoring of the crude reaction mixture demonstrat- (8.3 mg, 0.007 mmol, 4 mol%). The reaction vessel was
flushed with Ar and sealed. Through the septumanhydrous
ed that no competing carbon–carbon coupling occurs
and degassed THF (1.8 mL) was added. The mixture was
subsequently heated in a microwave reactor at 1008C for
at the thioamide or bromide positions in these Pd-
free transformations. Coupling at the reactive hetero-
aryl bromide position, however, was achieved by per-
forming base-catalyzed Suzuki–Miyaura cross-cou-
plings with aryl bromides 2 and 3. The expected
biaryl products 4 and 5 were obtained in excellent
yields (Scheme 1).
1
h. After this period an additional amount of Pd catalyst
(
8.3 mg, 0.007 mmol, 4 mol%) was added and the reaction
mixture was again heated at 1008C for 1 h. After cooling,
the solvent was evaporated and CHCl (90 mL) was added.
3
The crude reaction mixture was subsequently washed with
25% aqueous ammonia (3”30 mL). The aqueous ammoni-
umlayer was reextracted with CHCl 3 (3”30 mL). The com-
As far as the mechanism for carbon–sulfur cross-
coupling is concerned we suggest that for cyclic thio- bined organic phase was dried with MgSO and the residue
4
after evaporation purified by flash chromatography. Further
details can be found in the Supporting Information.
amides a mechanism that involves initial oxidation of
the thioamide to a disulfide species promoted by the
[
16b]
Cu(II) reagent is in operation.
The transient for-
Procedure for Carbon–Sulfur Cross-Coupling of 5-
Bromopyridine-(1H)-thione (1) with Phenylboronic
Acid (Scheme 1)
mation of a disulfide species in the conversion of thio-
amide 1 to the cross-coupled product 3 was clearly
evident by monitoring the reaction mixture by HPLC
and confirmed by an independent synthesis. As re-
A microwave process vial was charged with a stir bar. To
the disulfide may subsequently the vessel were added 5-bromopyridine-(1H)-thione
1
[16b,23]
cently suggested,
undergo Cu(I)-catalyzed cross-coupling with the bor- (30 mg, 0.16 mmol), PhB(OH)2 (77 mg, 0.63 mmol), Cu-
onic acid to produce the desired sulfide 3 in addition
to equal amounts of a catalytically inactive Cu(I) thio-
late (A, Figure 1), resulting in the observed empirical
requirement for stoichiometric amounts of Cu(I). We
have confirmed by an independent experiment that
the disulfide intermediate undergoes efficient carbon–
sulfur cross-coupling with phenylboronic acid in the
presence of a stoichiometric amount of a Cu(I) spe-
A
H
R
U
G
(28.7 mg, 0.16 mmol), 1,10-phenanthroline (56.9 mg,
2
0
mixture was stirred under air. After 15 min the reaction
vessel was sealed and irradiated at 1108C for 2 h. After
cooling, the mixture was transferred to a round-bottom
flask, and was adsorbed on silica gel. The residue was puri-
fied by flash chromatography on silica gel (CH Cl /hexanes
2
2
[11]
1
:1) to provide 5-bromo-2(phenylthio)pyridine 3
as a
1
semi-solid; yield: 71%. H NMR ([DMSO-d , 360 MHz):
6
cies such as CuTC. Overall product yields higher than d=8.53 (d, J=2.5 Hz, 1H), 7.88 (dd, J =8.6 Hz, J =2.5 Hz,
1
2
5
0% however, in this process can only be realized in 1H), 7.60–7.57 (m, 2H), 7.51–7.49 (m, 3H), 6.91 (d, J=
the presence of air, if the Cu(I) thiolate is then pre- 8.6 Hz, 1H); MS (pos. APCI): m/z=267.9.
sumably oxidized to a Cu(II) species which is able to
undergo further coupling with the boronic acid as re- Supporting Information
[
22]
cently proposed by Taniguchi.
General experimental details and characterization data
NMR, MS) for all new products.
In conclusion, we have developed a general Pd-cat-
alyzed protocol for the desulfitative carbon–carbon
cross-coupling of cyclic thioamides with boronic acids.
The method is applicable to a range of aromatic and
non-aromatic six-membered and five-membered
cyclic thioamides. We have also shown that the selec-
tivity of cyclic thioamides in their cross-couplings with
boronic acids can be tuned either toward carbon–
carbon cross-coupling using non-oxidative Pd(0)/
Cu(I) conditions, or toward carbon–sulfur cross-cou-
pling employing Cu(II) in the presence of oxygen.
(
Acknowledgements
This work was supported by the Austrian Science Fund
(
(
FWF) and the Austrian Academic Exchange Service
OeAD).
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
451

Hana Prokopcovµ and C. Oliver Kappe
UPDATES
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[
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[
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www.asc.wiley-vch.de
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 448 – 452