Palladium-catalyzed intermolecular desulfinylative cross-coupling of heteroaromatic sulfinates

Article abstract of DOI:10.1002/chem.201204201

Beauty lies in simplicity: An efficient and environmentally benign palladium-catalyzed protocol has been developed using a sulfinate as a nucleophilic coupling partner. The sulfinate position is arylated chemoselectively in very good yields. The bench-stable, non-hygroscopic heteroaromatic sulfinate salts rapidly undergo cross-coupling without the need of a co-catalyst, base, or additives (see scheme; mw=microwave). Copyright

Full text of DOI:10.1002/chem.201204201

DOI: 10.1002/chem.201204201
Palladium-Catalyzed Intermolecular Desulfinylative Cross-Coupling of
Heteroaromatic Sulfinates
Stꢀphane Sꢀvigny and Pat Forgione*[a]
C2-arylated heteroaromatics are an important class of
compounds with extensive use in diverse fields such as ad-
vanced materials,[1] organic light-emitting transistors
(OLETs),[2] solar cells,[3] natural products,[4] and medicinal
chemistry[5] (Scheme 1).
The development of simple and sustainable chemistry is
important as there continues to be an increasing demand on
non-renewable resources. Annually the refinement of petro-
leum generates over 40000 gigagrams (Gg) of SO2 waste
worldwide.[6] Exploiting this untapped resource of SO2 to
access key motifs such as C2-arylated heteroaromatics using
sulfinic acids would be environmentally beneficial. These
C2-arylated heteroaromatic motifs are most commonly ac-
cessed by classical palladium-catalyzed cross-couplings,[7]
such as the Suzuki–Miyaura[8] and Stille[9] couplings,
amongst others[7b,10] that continue to attract attention.[11] An
increasing amount of effort has been devoted to developing
[12]
À
more sustainable alternatives, such as C H-activated and
decarboxylative[13] cross-couplings. Direct C H arylations
are facile and do not require pre-functionalization, but can
À
À
lead to regioselectivity issues when similarly reactive C H
bonds are present.[14] Although a broad range of C2-arylated
heteroaromatics can be generated by decarboxylative cross-
coupling, the procedure suffers certain challenges. Nonethe-
less, decarboxylative couplings continue to attract significant
attention,[5a,15] leading to the development of elegant advan-
ces employing copper and/or silver as co-catalysts.[13c,d] De-
veloping an alternative to carboxylic acids with analogous
yet complementary reactivity led us to investigate sulfinic
acids. The decarboxylative cross-coupling of 2-heteroaro-
matic carboxylic acids was postulated to generate a key C2-
electrophilic palladation intermediate by a mechanism that
is dependent on the p-nucleophilicity of the system.[13e] DFT
calculations[16] demonstrate similarities between the HOMO
of thiophene-2-sulfinic acid and thiophene-2-carboxylic acid
(Figure 1).[17] However, the model suggests that the sulfinic
Scheme 1. Selected examples that show the importance of C2-arylated
thiophenes. A) A photochromic DTE system (photoswitch),[1d] B) a 17ß-
HSD1 inhibitor,[5b] C) a natural product,[4] and D) a hole-transporting ma-
terial for multilayered EL devices.[1e]
[a] S. Sꢀvigny, Prof. Dr. P. Forgione
Chemistry and Biochemistry
Concordia University
7141 rue Sherbrooke O.
Montrꢀal, QC, H4B 1R6 (Canada)
Fax : (+1)(514)-848-2868
E-mail: pat.forgione@concordia.ca
Homepage: http://faculty.concordia.ca/forgione
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204201.
Figure 1. The HOMO of thiophene-2-carboxylic acid and of thiophene-2-
sulfinic acid.
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COMMUNICATION
Table 1. Optimization of reaction conditions.[a]
acid slightly bends the thiophene ring, disrupting aromaticity
and consequently increasing the p-nucleophilicity. Addition-
ally, the out-of-plane OH group of the sulfinic acid may
direct the palladium to the C2-position more efficiently.
Examples of sulfinates that are used as electrophilic cou-
pling partners in palladium-mediated cross-couplings has
been demonstrated,[18] although their use as nucleophilic
partners is rare.[19] A concern when utilizing sulfinic acids
lies in their instability, which is partly due to their intermedi-
ate oxidation state.[20] Alternatively, sulfinate salts provide
an important advantage owing to their bench stability and
non-hygroscopic nature, making them easy to handle start-
ing materials that reluctantly undergo redox chemistry.[20,21]
The hypothesis that heteroaromatic sulfinates can be used
as nucleophilic coupling partners in a catalytic process was
evaluated by subjecting thiophene-2-sulfinate to optimized
decarboxylative cross-coupling conditions (Scheme 2). It
Entry 4a [equiv] 2b [equiv] catalyst (Pd, 0.05 equiv)
[%] yield
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
1.5
1.5
1.5
1.5
1.5
2.0
2.0
2.0
2.0
2.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
[Pd
G
72[b]
69[c]
69
59
84
PdCl2/HP
[Pd
[Pd
PdCl2/PPh3 (1:4)
[Pd(PtBu3)2]
83
87[e]
70
9
10
11
91
93[f]
[a] Reactions were performed on a 0.20 mmol scale. [b] using nBu4NBr
(1.5 equiv), Cs2CO3 (1.0 equiv). [c] using nBu4NBr (1.5 equiv). [d] Using
Cs2CO3 (0.10 equiv). [e] Using wet DMF. [f] Utilizing 28 month old sulfi-
nate, stored open to air.
to efficiently undergo cross-coupling in a very good yield
without the need of additives, base,[13e] or co-catalyst.[23] Sul-
finates are known to undergo homo-coupling when treated
with a stoichiometric amount of palladium.[19a,24] Suspecting
this may be occurring and reducing the yield of the product,
excess sulfinate was employed, and the yield increased to
84% with 1.5 equiv (entry 5) and 91% with 2.0 equiv
(entry 10). Utilizing the more widely available and less ex-
pensive [Pd
results to [PdACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Scheme 2. Desulfinylative versus decarboxylative cross-coupling. Reac-
tion conditions: Heteroaromatic species 1 or 4a (0.20 mmol, 1.0 equiv),
bromobenzene 2a (0.40 mmol, 2.0 equiv), [PdACHTUNTGRNEUNG(PtBu3)2] (0.01 mmol,
tion showed tolerance to water when using wet DMF
(entry 8).[20] In situ generation of the catalysts from PdCl2
yielded the cross-coupling product employing both HP-
0.05 equiv), Cs2CO3 (0.20 mmol, 1.0 equiv), nBu4NBr (0.30 mmol,
1.5 equiv) in anhydrous DMF (2 mL) at 1708C for 8 min, microwave
(MW) irradiation.
AHCTUNGTERN(GNUN tBu)3BF4 (66%, entry 6) and PPh3 (70%, entry 9) as the
ligand. The bench-stable nature of the sulfinates was demon-
strated by coupling a 28 month old sulfinate left open to the
air, with little change in yield (93%, entry 11; vs. 91%,
entry 10).
The chemoselectivity of the desulfinylative cross-coupling
was demonstrated by utilizing various substituted thio-
phene-2-sulfinates, which generated the corresponding prod-
uct (Scheme 3, 3e–f) in good to excellent yields. Lithium
benzo[b]thiophene-2-sulfinate led to substantially reduced
yields (67%, 3c), which is most likely due to the reduced
electron richness of the benzo-fused aromatic system. Inter-
was previously established that thiophene-2-carboxylic acid
did not yield the desired cross-coupling product under these
conditions [Scheme 2, Eq (1)]. Rewardingly, the coupling of
lithium thiophene-2-sulfinate [Scheme 2, Eq (2)] provided
the corresponding product (13% yield by NMR spectrosco-
py), thus demonstrating that sulfinates are viable coupling
partners in a catalytic palladium-mediated cross-coupling.
Lithium thiophene-2-sulfinate (4a) and 4-bromobenzoni-
trile (2b) were selected as coupling partners for the optimi-
zation of reaction conditions (Table 1) to facilitate product
isolation. The initial conditions (entry 1) utilized [Pd-
estingly, lithium 3-methylthiophene-2-sulfinate led to
a
A
markedly reduced yield of 53% (3 f). This is complementary
to the analogous carboxylic acid examples previously ob-
served, where the addition of the C3 methyl group allowed
improved, rather than reduced, yields.[13e] The scope of the
reaction was extended to other heteroaromatics, and very
good yields of 85% (3g) and 73% (3h) were obtained when
employing furan-2-sulfinate and benzo[b]furan-2-sulfinate,
respectively.
ve.[13e,22] Rewardingly, an initial 72% yield of isolated prod-
uct was obtained. Because sulfinate salts were utilized as the
nucleophilic aryl source, the Cs2CO3 base was omitted, and
the product was obtained in comparable yields (69%,
entry 2). Subsequent removal of the nBu4NBr additive yield-
ed an identical result of 69% (entry 3), despite the fact this
additive was an essential component for the decarboxylative
cross-coupling. The advantage that heteroaromatic sulfinates
present as nucleophilic coupling partners lies in the ability
Variation of the electronic and steric nature of the aryl
bromides was subsequently evaluated. Altering the nitrile
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2257

S. Sꢀvigny and P. Forgione
Scheme 4. Competition experiments. Reaction conditions: 6 (1.5 equiv),
4c (1.5 equiv), 2b (1.0 equiv), [PdACHTNUGTREN(NUNG PtBu3)2] (0.05 equiv) in DMF at 1708C
for 8 min in mw.
acids is likely.[13e] The nucleophilic sulfinate may, similar to
carboxylates, chelate palladium by attack onto the electro-
À
À
philic palladium(II) intermediate X PdL Ar 7. A direct de-
À
À
sulfinylation (Path A) generating the Het(Ar) Pd Ar inter-
mediate 9 is speculated to occur. However, bending of the
thiophene ring owing to the sulfinic acid functionality im-
plies a more nucleophilic p-system, perhaps facilitating a C2
electrophilic palladation (Path B), generating intermediate
10. Subsequently, re-aromatization of the heteroaromatic
ring 10 to generate intermediate 9 occurs by the extrusion
of SO2. In both cases, the catalytic cycle is completed by re-
ductive elimination of intermediate 9, generating the aryl-
substituted heteroaromatic 3 exclusively at the sulfinate po-
sition. Although the sulfinato–palladium complex may bind
similarly to that of the carboxylic acid (Scheme 6, 8a and 8b
vs. 11a and 11b), evidence suggests that sulfinates preferen-
tially form sulfinato-S (8c and 8d) rather than sulfinato-O
complexes owing to the softer nature of sulfur.[26] Nonethe-
less, further mechanistic investigations are required to better
understand the mechanism.
Scheme 3. Reaction scope. Reactions were performed on a 0.20 mmol
scale; * using sodium thiophene-2-sulfinate salt.
position has a negligible impact on coupling yield (3b, 3i,j).
Other electron-withdrawing groups were employed at the
para positions and provided the product in good yield (3k
and 3l). Electron-rich systems, such as 4-bromoanisole, un-
derwent the cross-coupling less efficiently (53%, 3m) than
electron-deficient aryl bromides. Interestingly, electron-neu-
tral 1-bromonaphthalene generated substantially larger
amounts of cross-coupling product (94%, 3n) than induc-
tively activated aryl bromides (64%, 3k).
It has been shown computationally that it should be
easier to extrude SO2 than CO2.[25] To compare sulfinates
and carboxylic acids as coupling partners with aryl bromides,
two substrates known to undergo coupling efficiently were
chosen. Towards this aim, 3-methylthiophene-2-carboxylic
acid (6, Scheme 4) and lithium 5-methylthiophene-2-sulfi-
nate (4c) were selected and subjected to optimized decar-
boxylative cross-coupling conditions. The desulfinylative
cross-coupling product (5c) was detected exclusively by
crude GC-MS and 1H NMR spectroscopy. Importantly, no
decarboxylative cross-coupling product (5e) was observed
when omitting the additive and base, and the desulfinylative
product (5c) was obtained exclusively. These results demon-
strate the potential to selectively perform a desulfinylative
cross-coupling in the presence of a carboxylic acid.
A mechanism (Scheme 5) that is similar to one previously
proposed for the arylation of heteroaromatic carboxylic
Scheme 5. Proposed mechanism.
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Intermolecular Cross-Coupling
COMMUNICATION
À
Keywords: C C bond formation
heterocycles · palladium · sustainable chemistry
·
cross-coupling
·
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Experimental Section
Heteroaromatic sulfinate 4a–g (0.20–0.40 mmol, 1.0–2.0 equiv), aryl
halide 2b–h (0.20–0.40 mmol, 1.0–2.0 equiv), and [PdACTHNUGTRNEUNG(PtBu3)2]
(0.01 mmol, 0.05 equiv) were added to a 5 mL conical microwave vial
equipped with a spin-vein. DMF (2 mL) was then added and the vial was
pre-stirred for 30 s at 238C, followed by heating at 1708C for 8 min with
stirring. The crude cross-coupling solution was diluted with EtOAc
(50 mL). The organic layer was washed with a saturated NaCl aqueous
solution (2ꢂ50 mL), saturated NaHCO3 aqueous solution (2ꢂ50 mL),
distilled H2O (1ꢂ50 mL), and saturated NaCl aqueous solution (1ꢂ
50 mL). The combined aqueous phases were washed with EtOAc
(50 mL). The combined organic phases were dried over Na2SO4 and after
filtration the solvent was evaporated under reduced pressure and the
solid residue was purified by flash column chromatography to obtain the
pure product 3b–n.
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This work was funded by the Natural Sciences and Engineering Research
Council (NSERC) of Canada and Le Fonds de Recherche du Quebec,
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Received: November 24, 2012
Published online: January 4, 2013
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