A mild and efficient palladium-catalyzed cyanation of aryl mesylates in water or tBuOH/water

Article abstract of DOI:10.1002/anie.201005121

Cool and compatible: Aryl mesylates and tosylates underwent palladium-catalyzed cyanation under mild, aqueous conditions at 65-80°C (see scheme). In many cases, water could be used as the reaction medium without a cosolvent, and a variety of substituents R, such as keto, aldehyde, ester, free amine, and nitrile groups, remained intact during the transformation. Cy=cyclohexyl, Ms=methanesulfonyl, Ts=p-toluenesulfonyl.

Full text of DOI:10.1002/anie.201005121

Communications
DOI: 10.1002/anie.201005121
Cross-Coupling
A Mild and Efficient Palladium-Catalyzed Cyanation of Aryl Mesylates
in Water or tBuOH/Water**
Pui Yee Yeung, Chau Ming So, Chak Po Lau, and Fuk Yee Kwong*
Dedicated to Professor Albert S. C. Chan on the occasion of his 60th birthday
Aryl nitriles are structural motifs that frequently occur in
agrochemically useful and pharmaceutically active com-
pounds.[1] Their widespread synthetic utility is highlighted
by a myriad of possible nitrile transformations,[2] including the
synthesis of benzoic acids/esters, amides, amines, aldehydes,
and nitrogen-containing heterocycles.[3] Traditional methods
for preparing aromatic nitriles from the corresponding aryl
iodides/bromides or aryl diazonium salts are the Rosenmund–
von Braun[4] and Sandmeyer reaction,[5] respectively. These
reactions require a stoichiometric amount of CuCN at an
elevated temperature (typically 150–2508C), and involve
complicated workup procedures. The other industrial
method of choice is ammoxidation, whereby the correspond-
ing toluene derivatives are treated with oxygen and ammonia
at 330–5508C in the presence of a heterogeneous catalyst
under high pressure.[6]
A versatile alternative for the preparation of benzonitrile
derivatives with more complex substitution patterns is the
transition-metal-catalyzed cyanation of readily available aryl
halides.[7] Nickel, palladium, and recently copper catalysts
have been shown to be effective for this purpose.[8–18] Nickel
catalysts are more air- and moisture-sensitive, as well as less
functional-group-compatible than palladium complexes.
Copper-catalyzed cyanation has been successful with aryl
iodides and bromides, yet inferior with aryl chlorides. In 1973,
Takagi et al. reported the palladium-catalyzed cyanation of
aryl iodides/bromides in the presence of KCN and the catalyst
Pd(CN)2 at 1408C or above.[8] Since this pioneering study,
palladium-based methods have garnered most of the atten-
tion as a result of their better functional-group tolerance, air
stability, and high catalytic activity.[7a] The palladium-cata-
lyzed cyanation has mostly been explored with relatively
and other cyanating agents.[15] The palladium-catalyzed cyan-
ation of aryl chlorides remains problematic and is generally
only possible at high temperature (120–1608C).[13,16] In 2007,
Littke et al. reported milder cyanation conditions for aryl
chlorides with the Buchwald-type ligand rac-2-di-tert-butyl-
phosphanyl-1,1’-binaphthyl.[17]
Although the cyanation of aryl halides (mainly ArBr) is
quite well established, the popularity of pseudohalides (aryl
triflates) in cyanation reactions is limited.[18] Possible con-
straints of this process may the high cost of the triflating agent
(e.g. Tf2O; Tf = trifluoromethanesulfonyl), and the ease of
decomposition of aryl triflates under basic reaction condi-
tions, especially at higher reaction temperatures (120–1608C).
However, the development of phenolic derivatives for use as
electrophilic reaction partners is worthwhile, since they may
offer different or unique substitution of the aromatic ring. The
corresponding aryl halides may not be commonly available or
may require additional synthetic steps to manipulate the
substitution pattern. Thus, the use of aryl mesylates or
arenesulfonates, which are less expensive and more stable
than aryl triflates, as cyanation substrates could be highly
favorable.[19] Nickel-mediated catalytic processes with aryl
mesylates were reported by Percec and co-workers in 1995.[20]
Although aryl mesylates have several beneficial features, no
palladium-catalyzed cyanation has been reported previously.
Herein, we report the first general palladium-catalyzed
cyanation of aryl mesylates. The reaction temperature of
808C is the mildest ever reported for the cross-coupling of
aryl mesylates. Moreover, this cyanation reaction was carried
out in an environmentally benign solvent: water or a water/
tBuOH solvent mixture.
We initially investigated the palladium-catalyzed cyana-
tion of electronically neutral 4-tert-butylphenyl mesylate as
the benchmark substrate in the presence of a series of
commercially available ligands, as well as our previously
developed indolylphosphines (Scheme 1). Poor conversion of
the aryl mesylate was observed with the phosphine ligands
Xphos,[21] Brettphos,[22] and Sphos,[23] whereas the ligands
Catacxium A[24] and Catacxium PCy[25] did not promote the
cyanation reaction. The aminophosphine L1 and the
straightforward aryl bromide substrates in the presence of
[9]
cyanides M CN (M = alkali metal, trimethylsilyl,[10] Cu,[11]
À
Zn[12]), acetone cyanohydrin,[13] potassium ferrocyanide(II),[14]
[*] P. Y. Yeung, Dr. C. M. So, Prof. Dr. C. P. Lau, Prof. Dr. F. Y. Kwong
State Key Laboratory of Chirosciences and
Department of Applied Biology and Chemical Technology
The Hong Kong Polytechnic University
Hung Hom, Kowloon, Hong Kong (Hong Kong)
Fax: (+852)23649932
E-mail: bcfyk@inet.polyu.edu.hk
À
C P-type phosphines L2 and L3 with a phosphanyl group at
the 3-position of the indole were also found to be inferior
ligands for the desired reaction.[26] However, with the ligand
CM-phos,[27] in which the phosphanyl unit is attached to the
non-indolyl ring, the desired product was formed in 90%
yield.
[**] We thank the Research Grants Council of Hong Kong
(PolyU 5008/08P) and the University Grants Committee Areas of
Excellence Scheme (AoE/P-10/01) for financial support and are
grateful for a PolyU Internal Competitive Research Grant (A-PG13).
We carried out a series of screening experiments to
optimize the reaction parameters (Table 1). A control experi-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201005121.
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Table 2: Palladium-catalyzed cyanation of aryl mesylates.[a]
Entry ArOMs
ArCN
Solvent
Yield[b]
[%]
1
water
tBuOH/
H2O
90
88
2[c]
3
4
water
water
96
84
5
6
water
water
84
72
tBuOH/
H2O
7
8
91
82
tBuOH/
H2O
tBuOH/
H2O
9
72
67
tBuOH/
H2O
Scheme 1. Ligand screening for the palladium-catalyzed cyanation of
4-tert-butylphenyl mesylate. Reaction conditions: aryl mesylate
(1.0 mmol), K4[Fe(CN)6]·3H2O (0.5 mmol), Pd(OAc)2 (0.02 mmol,
2 mol%), L (8 mol%; Pd/L 1:4), K2CO3 (0.125 mmol), water/tBuOH
(1:1, 4 mL total), 808C, 18 h. Yields were determined by GC with
dodecane as the internal standard. Cy=cyclohexyl.
10
tBuOH/
H2O
11
81
tBuOH/
H2O
12
13
95
86
Table 1: Initial screening of the palladium-catalyzed cyanation of a non-
tBuOH/
H2O
activated aryl mesylate.[a]
Entry Base
“CN” source
Solvent
Yield [%][b]
tBuOH/
H2O
14
15
87
93
1
2
3
K2CO3
K4[Fe(CN)6]·3H2O tBuOH/H2O (1:1) 90
Na2CO3 K4[Fe(CN)6]·3H2O tBuOH/H2O (1:1) 86
Cs2CO3 K4[Fe(CN)6]·3H2O tBuOH/H2O (1:1) 88
NaOtBu K4[Fe(CN)6]·3H2O tBuOH/H2O (1:1) 10
tBuOH/
H2O
4
5
6
7
8
KOtBu
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K4[Fe(CN)6]·3H2O tBuOH/H2O (1:1) 52
K4[Fe(CN)6]·3H2O tBuOH/H2O (1:1) 90
NaCN
CuCN
Zn(CN)2
K4[Fe(CN)6]·3H2O tBuOH
K4[Fe(CN)6]·3H2O MeCN/H2O (1:1)
K4[Fe(CN)6]·3H2O dioxane/H2O (1:1) 88
[a] Reaction conditions: ArOMs (1.0 mmol), K4[Fe(CN)6]·3H2O
(0.5 mmol), Pd(OAc)2 (0.02 mmol, 2 mol%), Pd/CM-phos (1:4), K2CO3
(0.125 mmol), water (2.0 mL) or water/tBuOH (3:1, 4.0 mL total), 808C,
18 h (the reaction time was not optimized for each substrate). [b] Yield of
the isolated product. [c] The reaction was carried out at 658C for 24 h.
tBuOH/H2O (1:1)
tBuOH/H2O (1:1)
tBuOH/H2O (1:1)
0
0
2
3
89
9
10
11
12
[a] Reaction conditions: 4-tert-butylphenyl mesylate (1.0 mmol), cyanide
source (K4[Fe(CN)6]·3H2O: 0.5 mmol; NaCN, CuCN, Zn(CN)2:
2.0 mmol), Pd source (0.02 mmol, 2 mol%), CM-phos (8 mol%,
Pd/CM-phos 1:4), base (0.125 mmol), solvent (4.0 mL total), 808C,
18 h. [b] The yield was determined by GC with dodecane as the internal
standard.
with NaOtBu and KOtBu provided the product in poorer
yield (Table 1, entries 1–6). The cyanide sources NaCN,
CuCN, and Zn(CN)2 did not promote the reaction (Table 1,
entries 1 versus 7–9). We initially attempted the cyanation
with tBuOH as the solvent. However, essentially no con-
version of the aryl mesylate was observed under our
cyanation conditions (Table 1, entry 10). We considered that
these poor results might be attributed to low solubility of the
cyanide source. Therefore, we added water as a cosolvent to
the reaction system in attempt to improve the solubility of the
ment revealed that no cyanation product was formed in the
absence of either the palladium catalyst or CM-phos.
Inorganic bases were found to assist the cyanation. Carbo-
nated bases and K3PO4 were superior, whereas the reactions
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Table 3: Palladium-catalyzed cyanation of aryl tosylates.[a]
hydrated K4[Fe(CN)6] reagent.
Under these conditions, the yield
of the aryl nitrile increased dramat-
ically to 90% (Table 1, entry 1).
Inspired by these results, we con-
ducted further experiments to
determine the best solvent ratio
(see the Supporting Information).
Surprisingly, the reaction even pro-
ceeded in water without a cosol-
vent.
Entry
ArOTs
ArCN
Solvent
Yield[b] [%]
1
2
water
tBuOH/H2O
trace
94
3
tBuOH/H2O
69
4
tBuOH/H2O
84
To test the effectiveness of our
catalytic system, we examined the
transformation of a variety of aryl
mesylates under the optimized
5
6
7
tBuOH/H2O
tBuOH/H2O
tBuOH/H2O
89
85
43
reaction
conditions
(Table 2).
Water was used as the only solvent
when the substrates were soluble at
808C (Table 2, entries 1 and 3–6).
When the reaction temperature was
lowered to 658C, the reaction still
proceeded well and gave the
desired product in good yield
(Table 2, entry 2). However, in that
case a tBuOH/water mixture was
necessary as the reaction medium.
Common functional groups, such as
keto, ester, and nitrile groups, were
compatible with the reaction con-
ditions (Table 2, entries 3–11).
Deactivated para-methoxyphenyl
mesylate was a suitable coupling
partner (Table 2, entry 7). The
cyanation of benzothiazolyl and
quinolyl mesylates furnished the
corresponding products in excellent
yields (Table 2, entries 12–14).
Notably, the cyanation of an unpro-
8
9
tBuOH/H2O
tBuOH/H2O
tBuOH/H2O
92
96
87
10
11[c]
tBuOH/H2O
71
[a] Reaction conditions: ArOTs (1.0 mmol), K4[Fe(CN)6]·3H2O (0.5 mmol), Pd(OAc)2 (0.02 mmol,
2 mol%), Pd/CM-phos (1:4), K2CO3 (0.125 mmol), tBuOH/H2O (1:1, 2.0 mL total), 808C, 18 h (the
reaction time was not optimized for each substrate). [b] Yield of the isolated product. [c] Pd(OAc)2:
5 mol%. Ts=p-toluenesulfonyl.
tected indole afforded the nitrile product in 93% yield
(Table 2, entry 15).
an N-aryl aminobenzonitrile from the tosylate derived from
3-aminophenol by cyanation of the aryl tosylate and subse-
quent N-arylation of the amino group (Scheme 2).
In summary, we have demonstrated the palladium-cata-
lyzed cyanation of aryl mesylates. The reaction temperature
To further extend our catalytic system, we also tested an
array of aryl tosylates (Table 3). Interestingly, the reaction did
not proceed when water was used as the only solvent (Table 3,
entry 1 versus Table 2, entry 1) owing to the low solubility of
the aryl tosylates. Hence, we used an organic cosolvent and
finally identified the optimal reaction medium as a 1:3
tBuOH/water mixture. The yield was significantly improved
(Table 3, entry 2). Ester, keto, aldehyde, and free amino
groups were compatible with the reaction conditions (Table 3,
entries 3–6). Not only aryl tosylates, but also an alkenyl
tosylate was a suitable substrate for the cyanation reaction
(Table 3, entry 11).
The manipulation of functionalized intermediates in a
reaction sequence is crucial in organic synthesis.[28] Under the
reaction conditions for cyanation, common functional groups
were tolerated well. Thus, it is possible to incorporate other
functional groups, such as an NH2 moiety, in the substrate for
a further coupling reaction. To demonstrate the feasibility of
this approach, we carried out a one-pot sequential synthesis of
Scheme 2. One-pot sequential cyanation–amination reaction. After the
cyanation reaction (conditions in Table 2, 18 h), 4-tBuC6H4OMs
(1.2 mmol) and K2CO3 (2.5 mmol) were added under N2, and the
reaction mixture was stirred at 1108C for an additional 24 h.
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[10] For selected references, see: a) M. Sundermeier, S. Mutyala, A.
of 808C is the mildest ever reported for the coupling of aryl
mesylates. Interestingly, the use of water as the solvent or a
cosolvent was found to be essential. This palladium catalyst
system exhibits excellent functional-group tolerance: nitrile,
ester, keto, aldehyde, free amine, and heterocyclic groups
remained intact during the course of reaction. Moreover, this
system is also applicable to the cyanation of aryl and alkenyl
tosylates. A one-pot cyanation–amination sequence demon-
strated the suitability of this reaction for the introduction of a
nitrile group and manipulation of a further functional group
in a synthetic pathway without isolation of the initial nitrile-
substituted intermediate. Given the practical advantages of
these sulfonating agents and the favorable cyanation con-
ditions, we believe that this method will find widespread use
in organic synthesis.
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Received: August 16, 2010
Published online: October 8, 2010
Keywords: cross-coupling · cyanation · mesylates · palladium ·
.
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