The palladium-catalyzed desulfitative cyanation of arenesulfonyl chlorides and sodium sulfinates

Article abstract of DOI:10.1039/c1cc16134b

A palladium-catalyzed desulfitative cyanation of arenesulfonyl chlorides and sodium sulfinates has been developed, providing aryl nitriles in moderate to excellent yields. It represents a facile procedure to access aryl nitriles.

Full text of DOI:10.1039/c1cc16134b

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COMMUNICATION
The palladium-catalyzed desulfitative cyanation of arenesulfonyl chlorides
and sodium sulfinatesw
Jianbin Chen, Yang Sun, Bin Liu, Dongfang Liu and Jiang Cheng*
Received 2nd October 2011, Accepted 31st October 2011
DOI: 10.1039/c1cc16134b
A palladium-catalyzed desulfitative cyanation of arenesulfonyl
chlorides and sodium sulfinates has been developed, providing
aryl nitriles in moderate to excellent yields. It represents a facile
procedure to access aryl nitriles.
using arenesulfonyl chlorides and sodium sulfinates in the
cyanation reactions have never been reported before. Inspired
by the advantages of desulfitative coupling, we envisioned that
arenesulfonyl chlorides and sodium sulfinates may undergo
desulfitative cyanation with CuCN to access aryl nitriles.
Herein, we report our study on such a transformation.
Aromatic nitriles are ubiquitous structural motifs that frequently
occur in agrochemically useful and pharmaceutically active
compounds.1 Moreover, nitriles are highly useful in the field
of synthetic chemistry because of their possible transformations
to benzoic acids/esters, amines, amides, benzamidines, and
heterocycles.2 As a consequence, the synthesis of nitriles has
been an interest of chemists for several decades. Traditionally,
the nitriles have been formed by the Rosenmund–von Braun and
Sandmeyer reactions involving stoichiometric copper(I) cyanide
and aryl halides or diazonium salts, respectively (Scheme 1).3
However, these processes suffer from drawbacks such as high
temperature, high pressure or limited substrate scope with
regard to reaction conditions, complicated workups.
Initially, 4-methoxybenzene-1-sulfonyl chloride (1a) was
chosen as a model substrate to screen for optimal reaction
conditions. Fortunately, the first glimpse of success was
obtained by using the combination of a catalytic amount of
Pd(CH3CN)2Cl2 and Cu(OAc)2 in 1,4-dioxane, whereupon 2a
was isolated in 11% yield (entry 1, Table 1). During the
screening of copper sources, Cu2O showed higher activity than
CuI, CuCl2 and CuBr2. Notably, the use of Cu(acac)2 furnished
the desired product 2a in an excellent yield (the yield dramatically
increased to 91%, entries 2–6, Table 1). The influence of bases was
Table 1 Selected results of reaction parameters screeninga
Recently, the transition-metal-catalyzed cyanation of C–H bonds
represents a promising strategy to access aryl nitriles.4 However,
due to the requirement of a directing group, the substrate scope is
somewhat limited. A practical alternative method involves the
transition-metal-catalyzed cyanation of ArX (X = I, Br, Cl,
OTf,5 OMs,6 and B(OH)27) with metal or organic cyanide and safe
cyanide sources.8 Meanwhile, arenesulfonyl chlorides and sodium
sulfinates are readily available compounds and coupling partners in
transition-metal-catalyzed cross-coupling reactions to undergo
desulfitative Suzuki–Miyaura,9 Stille and carbonylative Stille,10
Mizoroki–Heck,11 Sonogashira–Hagihara,12 Negishi13 and other
reactions.14 However, to the best of our knowledge, examples of
Entry Pd source
Cu source Base
Solvent
Yield (%)
1
Pd(CH3CN)2Cl2 Cu(OAc)2 Na2CO3 1,4-Dioxane 11
2
3
4
5
Pd(CH3CN)2Cl2 CuI
Pd(CH3CN)2Cl2 Cu2O
Pd(CH3CN)2Cl2 CuCl2
Pd(CH3CN)2Cl2 CuBr2
Na2CO3 1,4-Dioxane 35
Na2CO3 1,4-Dioxane 60
Na2CO3 1,4-Dioxane 33
Na2CO3 1,4-Dioxane 15
6
7
Pd(CH3CN)2Cl2 Cu(acac)2 Na2CO3 1,4-Dioxane 91
Pd(CH3CN)2Cl2 Na2CO3 1,4-Dioxane 62
—
8
9
Pd(CH3CN)2Cl2 Cu(acac)2 KHCO3 1,4-Dioxane 82
Pd(CH3CN)2Cl2 Cu(acac)2 K2CO3 1,4-Dioxane 85
Pd(CH3CN)2Cl2 Cu(acac)2 K3PO4 1,4-Dioxane 78
Pd(CH3CN)2Cl2 Cu(acac)2 NaOH 1,4-Dioxane 76
10
11
12
13
14
15
16
17
18
19
20
21
Pd(CH3CN)2Cl2 Cu(acac)2
—
1,4-Dioxane o5
Pd(CH3CN)2Cl2 Cu(acac)2 Na2CO3 DMF
Pd(CH3CN)2Cl2 Cu(acac)2 Na2CO3 Toluene
Pd(CH3CN)2Cl2 Cu(acac)2 Na2CO3 THF
o5
42
o5
Pd(CH3CN)2Cl2 Cu(acac)2 Na2CO3 Monoglyme o5
Pd(OAc)2
PdCl2
Pd(acac)2
Cu(acac)2 Na2CO3 1,4-Dioxane 10
Cu(acac)2 Na2CO3 1,4-Dioxane
Cu(acac)2 Na2CO3 1,4-Dioxane 15
6
Scheme 1 Cyanation methods.
Pd(PhCN)2Cl2 Cu(acac)2 Na2CO3 1,4-Dioxane 85
Cu(acac)2 Na2CO3 1,4-Dioxane o5
—
College of Chemistry & Materials Engineering, Wenzhou University,
Wenzhou 325000, People’s Republic of China.
E-mail: jiangcheng@wzu.edu.cn
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/c1cc16134b
a
Reaction conditions: 1a (0.2 mmol), CuCN (0.21 mmol), Pd sources
(10 mol%), Cu sources (20 mol%) and bases (0.4 mmol) in dry
1,4-dioxane (2 mL), air, 130 1C, sealed tube, 12 h, isolated yield.
c
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Chem. Commun., 2012, 48, 449–451 449

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Table 2 Desulfitative cyanation of arenesulfonyl chloridesa
Table 3 Desulfitative cyanation of sodium aryl sulfinatesa
Entry
1
Substrate
Product
Yield (%)
65
2a
2
3
4
2b
2c
2e
46
62
60
5
6
a
2g
2k
61
58
a
Reaction conditions: arenesulfonyl chloride 1a–k (0.2 mmol), CuCN
(0.21 mmol), Pd(CH3CN)2Cl2 (10 mol%), Cu(acac)2 (20 mol%) and
Na2CO3 (0.4 mmol) in dry 1,4-dioxane (2 mL), air, 130 1C, sealed tube,
24 h, isolated yield. 12 h.
Reaction conditions: sodium aryl sulfinates (0.2 mmol), CuCN
(0.21 mmol), Pd(CH3CN)2Cl2 (10 mol%), Cu(acac)2 (20 mol%) and
Na2CO3 (0.4 mmol) in dry 1,4-dioxane (2 mL), air, 130 1C, sealed tube,
24 h, isolated yield.
b
also investigated. Several common inorganic bases gave satisfying
results, and Na2CO3 was found to be the best, providing 2a in
excellent yield for all the above transformations (entries 6, 8–11,
Table 1). However, in the absence of a base, the procedure did not
furnish any product (entry 12, Table 1). Reactions in other solvents,
such as toluene, THF, 1,2-dimethoxyethane and DMF provided
lower yields or did not proceed (entries 13–16, Table 1). Except for
Pd(PhCN)2Cl2, other Pd sources, such as Pd(OAc)2, PdCl2,
and Pd(acac)2, showed low efficiencies (entries 17–20, Table 1).
The blank experiment confirmed that no cyanated product was
observed in the absence of Pd sources (entry 21, Table 1).
Prompted by the successful cyanation protocol, we then went
on to test the applicability of this method to sodium aryl sulfinates
(Table 3). As expected, this procedure was compatible with a
broad range of substrates. Notably, substrates bearing both
electron-withdrawing and electron-donating groups were all
successfully tolerated in this reaction. However, the yields were
lower than those of arenesulfonyl chlorides. Unfortunately, similar
to 2-nitrobenzenesulfonyl chloride and 2,4,6-triisopropylbenzene-
1-sulfonyl chloride, sodium 2-nitrobenzenesulfinate and sodium
To establish the scope of this developed cyanation protocol, we
tested a wide range of arenesulfonyl chlorides (Table 2). As
expected, various common functional groups, such as methoxy,
tert-butyl, phenyl, halo, acetyl and nitro groups, were well tolerated
with prolonged time. The procedure seemed insensitive to the
electronic nature of the substituents on the aromatic ring of the
arenesulfonyl chlorides. For example, substrates having electron-
donating groups, such as para-methoxy and phenyl, on the
aromatic ring of the sulfonyl chlorides gave 2a and 2d in excellent
yields, respectively; while substrates having a nitro group as a
strong electron-withdrawing group at the para and meta positions
of the aromatic ring also provided 2g and 2h in good yields. It is
noteworthy that halogen functional groups remained intact under
the standard procedures, offering handles for other valuable
manipulations (2e and 2f). Specifically, the free acetamido substrate
2j was obtained in low yield under the standard conditions,
which was at least partly due to the potential acidic proton.
However, the reaction was sensitive to steric effects surrounding
the highly congested arenesulfonyl chlorides. This was indeed the
case with 2-nitrobenzenesulfonyl chloride and 2,4,6-triisopropyl-
benzene-1-sulfonyl chloride, which gave 1-chloro-2-nitro-benzene
and 1,3,5-triisopropylbenzene, respectively. Disappointingly, para-
trifluoromethyl and cyano substituted arenesulfonyl chlorides
failed to deliver the cyanated products, providing only homo-
coupling symmetrical biaryl species.15
Scheme 2 Proposed mechanism.
c
450 Chem. Commun., 2012, 48, 449–451
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2,4,6-triisopropylbenzene-sulfinate also failed to deliver the
cyanated products.
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As far as sodium aryl sulfinates are concerned, a plausible
mechanism is illustrated in Scheme 2. Similar to the Pd(II)-
catalyzed desulfinylative reaction of arenesulfonyl chlorides,10
the proposed mechanism involves the following several steps:
(I) coordination of the sodium aryl sulfinates to palladium(II)
gives complex A; (II) the desulfitative reaction of complex A
generates aryl palladium complex B; (III) coordination of the
‘CN’ to B forms complex C; (IV) reductive elimination of the
intermediate C delivers the desired product 2 along with a
Pd(0) species, which is oxidized to Pd(II) by Cu(II) and/or air.
In conclusion, we have developed an efficient Pd-catalyzed
cyanation of arenesulfonyl chlorides and sodium sulfinates. The
reaction represents a convenient method with good functional
group tolerance for the synthesis of aromatic nitriles in medicinal
chemistry and materials science. Further studies are underway to
provide insight into the scope and mechanism of these arylsulfonyl
chloride functionalizations.
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¨
Financial support was provided by the National Natural
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Science Foundation of Zhejiang Province (No. R4110294).
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c
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Chem. Commun., 2012, 48, 449–451 451