Increasing the scope of palladium-catalyzed cyanations of aryl chlorides

Article abstract of DOI:10.1002/adsc.200800733

An improved protocol for the palladium-catalyzed cyanation of electron-rich aryl chlorides with potassium ferrocyanide [K₄[Fe(CN)₆]] is presented. Compared to previous procedures the substrate scope is significantly broadened.

Full text of DOI:10.1002/adsc.200800733

UPDATES
DOI: 10.1002/adsc.200800733
Increasing the Scope of Palladium-Catalyzed Cyanations of Aryl
Chlorides
a
a
a
a
Thomas Schareina, Ralf Jackstell, Thomas Schulz, Alexander Zapf,
b
b
a,
Alain Cottꢀ, Matthias Gotta, and Matthias Beller *
Leibniz-Institut fꢁr Katalyse e.V. an der Universitꢂt Rostock, Albert-Einstein-Str. 29A, 18059 Rostock, Germany
Fax : (+49)-381-1281-5000; e-mail: Matthias.Beller@catalysis.de
a
b
Saltigo GmbH, Building H5 ZeTO 2, 51369 Leverkusen, Germany
Received: November 26, 2008; Published online: February 18, 2009
[
4,5]
Abstract: An improved protocol for the palladium-
catalyzed cyanation of electron-rich aryl chlorides
with potassium ferrocyanide {K [Fe(CN) ]} is pre-
sented. Compared to previous procedures the sub-
strate scope is significantly broadened.
lyzed cyanations has gained considerable attention.
In 2004, we introduced potassium ferrocyanide
K [Fe(CN) ] as a novel cyanation reagent, which is in-
4
6
4
6
[6,7]
teresting both because of its price and low toxicity.
In fact, K [Fe(CN) ] is the most environmentally
4
6
benign cyanation source known to date and quickly
attracted substantial interest for various synthetic ap-
Keywords: aromatic substitution; aryl halides; CÀC
[
8]
plications. In addition to its environmental advan-
tages, it allows for improved catalyst productivity and
substrate scope. For example, catalyst turnover num-
bers of 18,000 are achieved without any ligand added
in the palladium-catalyzed reaction of relatively
coupling; cyanides; palladium
[
6b]
Introduction
simple aryl bromides.
Using copper as catalyst
metal in the presence of 1-alkylimidazoles as additives
In the last decade the use of palladium- and copper- functionalized aryl and heteroaryl bromides were con-
[
9]
catalyzed coupling reactions has proven to be a pow- verted in high yields, however aryl chlorides reacted
erful tool for the functionalization of arenes and het- only in rare cases. Nevertheless, initial success in the
[1]
eroarenes. Obviously, the general applicability of a cyanation of aryl chlorides has been achieved. Sakaki-
given coupling reaction both in academia and industry bara et al. have reported about nickel-based cyanation
is based mainly on a broad substrate scope and the reactions, unfortunately HMPA was found as the best
[
10]
availability of starting materials, ligands, and catalysts. solvent.
Due to efficient developments in the last decades Pd(OAc) /n-butyl-di(1-adamantyl)phosphine (Scheme
most coupling reactions of undemanding bromo- and 2, ligand 1) for reactions of aryl chlorides with non-re-
More recently, we reported the use of
AHCTUNGTRENNUNG
2
[
11]
iodoarenes proceed smoothly and numerous catalysts active substituents.
Most currently, Littke and co-
based on palladium and in some cases on copper are workers described the use of 4 mol% Pd and 8 mol%
known for these transformations. However, there of a special Buchwald-type ligand (Scheme 2, ligand
[12]
exists still a number of interesting substrates for the 2), Zn as additive, and Zn(CN) as cyanide source.
2
pharmaceutical and agrochemical industry, which So far, the use of palladium as catalyst metal seems
pose a significant challenge. For example, functional- indispensable for the conversion of aryl chlorides.
ized electron-rich aryl chlorides are desired substrates
for various cross-coupling reactions. Unfortunately, at
the same time, they constitute the most challenging Results and Discussion
substrates due to the high dissociation energy of the
2
[2]
C
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(sp )ÀCl bond, and it is generally accepted that Primary anilines and phenols are demanding sub-
electron-rich derivatives react more slowly than elec- strates for all kinds of CÀC coupling reactions, since
tron-poor ones.
[
3]
they may form CÀN or CÀO bonds. In addition,
Here, we report improved palladium catalysts amino and hydroxy groups are known to act as li-
based on bulky heterocyclic phosphines, which allow gands, blocking the reactive centre. In order to devel-
for efficient cyanations of “difficult” aryl chlorides op improved catalysts, 4-chloro-2,6-dimethylaniline
with potassium ferrocyanide. In recent years the syn- was chosen as a substrate of medium difficulty. The
thesis of benzonitriles via palladium- and copper-cata- respective cyanation served as a model reaction to
Adv. Synth. Catal. 2009, 351, 643 – 648
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
643

Thomas Schareina et al.
UPDATES
was used further on, since stock solutions are easily
prepared.
It should be noted that the reaction is highly sensi-
tive with respect to the amount and type of base.
Hence, changing from sodium carbonate to standard
inorganic bases commonly used in coupling reactions
led to significantly lower yields (Table 1, entries 7–
Scheme 1. Model reaction.
10). Even the concentration of base is important
(
Table 1, entry 11), despite the fact that, for purely
stoichiometric reasons, no base is needed. However,
in the absence of sodium carbonate no conversion is
observed (Table 1, entry 12). This suggests that the
base is involved in the formation of the reactive inter-
mediate.
Among the tested solvents NMP gave comparable
results to the standard solvent DMAc (Table 1, en-
tries 13–16). Although the use of potassium hexacya-
noferrate(II) hydrate was found to be advantageous
[
11,13]
in some cases,
crease of the yield occurred (Table 1, entry 19). More-
over, potassium hexacyanoferrate(III) was tested, but
in this model reaction a major de-
AHCTUNGTRENNUNG
also with low success (Table 1, entry 20).
Next, the influence of different electron-rich ligands
was investigated. Selected results are shown in
Table 2. A special focus has been given on biaryl-sub-
[
14,15]
stituted ligands.
As a general trend, dicyclohexyl-
substituted phosphines were not suitable, while di-
tert.-butyl-substituted and di-1-adamantyl-substituted
biarylphosphines led to higher yields. However, this is
difficult to understand and we have no conclusive ex-
planation why, e. g., t-Bu-XPhos (Scheme 2, ligand 4)
performed poorly, while the nominally less bulky tert.-
butyl-JohnPhos (Scheme 2, ligand 12) gave a yield of
59%.
Finally, the novel protocol has been proven success-
ful for the cyanation of diverse electron-rich and chal-
lenging aryl chlorides. Selected results of the scope
and limitations are shown in Table 3. In general, only
the two best results were included. It should be noted
that for certain substrates a proper adaption of the re-
action conditions might further improve the yield. For
2
5
-, 3-, and 4-chloroanisole (Table 3, entries 1–6) and
-chloro-1,3-benzodioxole (Table 3, entries 7 and 8),
Scheme 2. Ligands tested.
ligand 11 (tri-tert.-butylphosphine) gave the best re-
sults (48–83% yield), while imidazole-substituted li-
gands 14 and 15 led to 18–85% yield. With the differ-
study the influence of temperature, Pd content and ently substituted chloroanilines the new bulky phos-
different ligands (Scheme 1; Table 1). According to phine ligands 14–16 based on a heterocyclic frame-
our previous work a high-boiling, polar solvent, tem- work dominate leading to yields of 40–75% of the
peratures of 1408C and dried potassium hexacyano- corresponding benzonitrile. Notably, also free phenols
ferrate(II) were used in the presence of the sterically can be cyanated in significant to good yield in the
hindered heteroarylphosphine 3.
presence of the “right” ligand (Table 3, entries 19–21).
Initial variations of the palladium source showed And last but not least, with the sterically most hin-
that PdCl , Na PdCl , and Pd
A
H
U
G
R
N
U
G
2
2
4
2
sults than Pd ACHTUNGTRENNUNG( dba) and Pd ACHTUGNTRENNU(G allyl)Cl. The low perfor- tained in the presence of 1 (Table 3, entries 22 and
2 3
[11]
mance of Pd ACHTUNGTRENNUNG( OAc) corresponds with the findings of 23).
2
[12]
Littke et al. For reasons of practicability Pd ACHTGNUTERNN(UNG TFA)
2
644
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ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 643 – 648

Increasing the Scope of Palladium-Catalyzed Cyanations of Aryl Chlorides
UPDATES
[a]
Table 1. Cyanation of 4-chloro-2,6-dimethylaniline.
[b]
[b]
Entry
Solvent
T [8C]
Metal Precursor (mol% Pd)
Pd(TFA) (1)
Base (mol)
Conversion [%]
Yield [%]
[
c]
1
2
3
4
5
6
7
8
9
DMAc
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
120
160
140
140
A
H
U
G
R
N
U
G
Na CO (20)
82
65
78
75
72
33
61
52
38
33
39
2
30
59
30
28
71
44
12
29
61
50
66
65
28
26
13
6
15
21
30
0
20
59
20
11
54
37
6
2
2
3
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
Pd2
A
H
U
G
R
N
U
G
Na CO (20)
3
2 3
PdCl (1)
Na CO (20)
2 3
2
Na PdCl (1)
Na CO (20)
2
4
2 3
Pd
Pd(allyl)Cl (1)
Pd(TFA) (1)
Pd(TFA) (1)
Pd(TFA) (1)
Pd(TFA) (1)
Pd(TFA) (1)
Pd(TFA) (1)
Pd(TFA) (1)
Pd
Pd(TFA) (1)
Pd(TFA) (1)
Pd(TFA) (1)
Pd(TFA) (1)
Pd(TFA) (1)
Pd(TFA) (1)
A
H
U
G
R
N
N
(OAc) (1)
Na CO (20)
2 3
2
A
H
U
G
R
N
G
Na CO (20)
2 3
A
H
U
G
R
N
U
G
K CO (20)
2 3
[d]
2
A
H
U
G
R
N
U
G
Cs CO (20)
2 3
[d]
2
A
H
U
G
R
N
U
G
K PO (20)
2
3
4
[
d]
10
11
12
13
14
15
16
17
18
19
20
A
H
U
G
R
N
U
G
KF (20)
2
A
H
U
G
R
N
U
G
Na CO (50)
2
2
3
DMAc[
A
H
U
G
R
N
U
G
–
2
c]
DMSO
A
H
U
G
R
N
U
G
Na CO (20)
2
2
3
[c]
NMP[
A
H
U
G
R
N
N
(TFA) (1)
Na CO (20)
2
2 3
c]
DMF
A
H
U
G
R
N
U
G
Na CO (20)
2 3
2
[c]
dioxane
DMAc
DMAc
DMAc
DMAc
A
H
U
G
R
N
U
G
Na CO (20)
2
2 3
A
H
U
G
R
N
U
G
Na CO (20)
2 3
2
A
H
U
G
R
N
U
G
Na CO (20)
2
2 3
[
[
e]
f]
A
H
U
G
R
N
U
G
Na CO (20)
2 3
2
A
H
U
G
R
N
U
G
Na CO (20)
22
2
2
3
[
a]
General reaction conditions: 2 mmol 4-chloro-2,6-dimethylaniline, 2 mol% ligand 3, 20 mol% K [Fe(CN) ], 2 mL solvent,
4
6
1
00 mL tetradecane (internal standard for GC), other compounds and temperature as given in the table, heated for 16 h.
[
[
b]
Conversion and yield determined by GC as the average of two experiments.
All solvents were dried by standard procedures. DMAc=N,N-dimethylacetamide, DMSO=dimethyl sulfoxide, NMP=
N-methylpyrrolidone, dioxane=1,4-dioxane.
Stored and weighed in a glove box under argon.
K [Fe(CN) ] (20) instead of K [Fe(CN) ].
c]
[
[
[
d]
e]
f]
3
6
4
6
K [Fe(CN) ]·3H O (20) instead of K [Fe(CN) ].
4
6
2
4
6
Table 2. Influence of ligands on the cyanation of 4-chloro- Conclusions
[a]
2,6-dimethylaniline (table is ordered by ascending yield).
In summary, we have shown that electron-rich aryl
chlorides can be successfully converted to benzoni-
triles in the presence of palladium/phosphine catalysts
applying the environmentally benign cyanide source
K [Fe(CN) ]. Of special importance is the cyanation
[b]
[c]
[c]
Ligand (mol%)
Conversion [%]
Yield [%]
1
2
3
4
5
6
7
8
9
1
1
1
1
4 (2)
5 (2)
1 (2)
2 (2)
6 (2)
7 (2)
9 (2)
10 (2)
11 (2)
12 (2)
13 (2)
8 (2)
14 (2)
10
17
24
30
25
30
30
35
77
79
76
95
91
7
10
16
18
20
22
25
26
59
59
63
73
75
4
6
of difficult substrates such as chlorophenols and
chloroanilines. Nevertheless, so far one universally ap-
AHCTUNGTRENNUNG
plicable catalyst system for the cyanation of aryl
chlorides is not yet available. In this respect the novel
bulky heterocyclic phosphine ligands represent a vari-
able class of phosphine ligands, which are easily tuna-
ble and show good prospects not only for cyanation
reactions, but also for other cross-coupling reactions
0
1
2
3
[
16]
of aryl chlorides.
[
a]
General conditions: 2 mmol 4-chloro-2,6-dimethylaniline,
2
1
mol% ligand, 20 mol% K [Fe(CN) ], 2 mL DMAc,
00 mL tetradecane (internal standard for gc), 20 mol%
4 6
Experimental Section
Na CO , 1408C, 16 h.
2
3
[
b]
Conversion and yield determined by GC as the average
of two experiments.
General Procedures
K [Fe(CN) ]·3H O was ground to a fine powder and dried
4
6
2
under vacuum (ca. 2 mbar) at 808C overnight. This material
was stored in a stoppered bulb and could be used for
Adv. Synth. Catal. 2009, 351, 643 – 648
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
645

Thomas Schareina et al.
UPDATES
[a]
Table 3. Cyanation of various electron-rich aryl chlorides.
Entry
Substrate
Solvent
Metal Precursor (mol% Pd)
Pd(TFA) (1)
Ligand (mol%)
Conversion [%]
Yield [%]
1
2
DMAc
DMAc
A
H
U
G
E
N
N
11 (2)
14 (2)
48
20
48
18
2
Pd(TFA) (1)
ACHTUNGTRENNUNG
2
3
4
DMAc
DMAc
Pd
A
H
U
G
R
N
U
G
11 (2)
15 (2)
90
76
83
68
2
Pd(TFA) (1)
AHCTUNGTRENNUNG
5
6
DMAc
DMAc
Pd
A
H
U
G
E
N
N
(TFA) (1)
3 (2)
11 (2)
90
83
85
83
2
Pd(TFA) (1)
A
H
U
G
R
N
U
2
7
8
DMAc
DMAc
Pd
A
H
U
G
R
N
U
G
14 (2)
11 (2)
60
52
58
52
2
Pd(TFA) (1)
AHCTUNGTRENNUNG
9
DMAc
DMAc
PdCl (1)
15 (2)
14 (2)
75
78
55
40
2
10
Pd ACHTUNGERTNNUNG( TFA) (1)
2
1
1
1
2
DMAc
DMAc
Pd
A
H
U
G
R
N
U
G
11 (2)
16 (2)
73
84
54
45
2
Pd(TFA) (1)
AHCTUNGTRENNUNG
1
1
3
4
NMP
DMAc
Pd
A
H
U
G
E
N
N
(TFA) (1)
3 (2)
16 (2)
73
69
67
59
2
Pd(TFA) (1)
A
H
U
G
R
N
U
2
1
1
5
6
DMAc
DMAc
Pd
A
H
U
G
R
N
U
G
16 (2)
14 (2)
84
75
65
49
2
Pd(TFA) (1)
AHCTUNGTRENNUNG
1
1
7
8
DMAc
DMAc
Pd
A
H
U
G
R
N
U
G
14 (2)
8 (2)
91
95
75
73
2
Pd(TFA) (1)
AHCTUNGTRENNUNG
19
DMAc
Pd
A
H
U
G
R
N
U
G
11 (2)
63
44
2
2
2
0
1
DMAc
DMAc
Pd
A
H
U
G
E
N
N
(TFA) (1)
3 (2)
14 (2)
78
77
61
60
2
Pd(TFA) (1)
A
H
U
G
R
N
N
2
2
2
2
3
DMAc
DMAc
Pd
A
H
U
G
E
N
N
(TFA) (1)
1 (2)
16 (2)
87
43
76
37
2
Pd(TFA) (1)
A
H
U
G
R
N
N
2
[
a]
General reaction conditions: 2 mmol aryl chloride, 2 mol% ligand, 20 mol% K [Fe(CN) ], 2 mL DMAc, 100 mL tetrade-
4
6
cane (internal standard for GC), 20 mol% Na CO , 1408C, 16 h.
2
3
months without noticeable decreases in activity. NMP and
DMAc were distilled from CaH2 under reduced pressure
and stored under argon. DMSO was fractionally distilled
under reduced pressure. Dioxane was dried over sodium
benzophenone ketyl, distilled and stored under argon.
Ligands 1, 2, 4–6 and 9–13 are commercially available. Li-
Data of ligand 3 {2-(di-tert.-butylphosphino)-1-[2-(trime-
1
thylsilyl)phenyl]-1H-pyrrole}: H NMR (CDCl , 400 MHz):
3
d=0.00 [s, 9H, Si ACHTNUGTRNEUN(G CH ) ], 1.80 {d, 18H, P[C AHTCUNGERTNNUNG( CH ) ] }, 6.6 (d,
3 3 3 3 2
13
1H), 6.8 (d, 1H), 7.2 (m, 2H), 7.40–7.50 (m, 3H); C NMR
(CDCl , 100 MHz): d=0.0, 30.6, 33.1, 117.4, 118.8, 128.3,
3
130.5, 134.9, 138.3, 142.7; HR-MS: m/z=359.21875, calcd.
[15a]
[16]
[16]
gands 3 (see below), 7,
8,
14–16
were available as
for C H NPSi: 359.21982.
2
1
34
test samples in our group. All other materials were pur-
chased from different chemicals providers (Aldrich, Fluka,
Alfa-Aesar etc.) and used as received.
646
asc.wiley-vch.de
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 643 – 648

Increasing the Scope of Palladium-Catalyzed Cyanations of Aryl Chlorides
UPDATES
Typical Catalytic Procedure
M. Beller, Chem. Eur. J. 2003, 9, 1828–1836; g) H. R.
Chobanian, B. P. Fors, L. S. Lin, Tetrahedron Lett. 2006,
1
48 mg (0.4 mmol) dry K [Fe(CN) ], base, palladium source,
4 6
4
7, 3303–3306; h) R. S. Jensen, A. S. Gajare, K.
Toyota, M. Yoshifuji, F. Ozawa, Tetrahedron Lett. 2005,
6, 8645–8648; i) J. M. Veauthier, C. N. Carlson, G. E.
Collis, J. L. Kiplinger, K. D. John, Synthesis 2005, 2683–
ligand, and 2 mmol aryl chloride were placed in an Ace
pressure tube under argon. Thereafter, 100 mL tetradecane
4
(
internal standard for GC) and 2 mL solvent were added
and the mixture was stirred for 1 min. The pressure tube
was sealed and heated for 16 h at the temperature specified
in the tables. After cooling to room temperature 3 mL ethyl
acetate were added and the mixture was analyzed by GC.
Conversion and yield were calculated as average of 2 paral-
lel runs. For isolation of the products the reaction mixture
was transferred to a separation funnel with the help of an
appropriate non-water miscible solvent and washed with
water. In experiments with >10 mmol of substance often a
dark bluish precipitate and emulsions were formed, which
conceal the interface and lengthen the work-up. In these
cases, a filtration over a sintered glass frit removes both.
The organic phase was dried over Na SO . After evapora-
2
1
686; j) R. Chidambaram, Tetrahedron Lett. 2004, 45,
441–1444; k) H. J. Cristau, A. Ouali, J. F. Spindler, M.
Taillefer, Chem. Eur. J. 2005, 11, 2483–2492; l) B. Tylle-
man, R. Gomez-Aspe, G. Gbabode, Y. H. Geerts, S.
Sergeyev, Tetrahedron 2008, 64, 4155–4161; m) P.
Ryberg, Org. Process Res. Dev. 2008, 12, 540–543;
n) Z. Iqbal, A. Lyubimtsev, M. Hanack, Synlett 2008,
2
287–2290; o) S. Challenger, Y. Dessi, D. E. Fox, L. C.
Hesmondhalgh, P. Pascal, A. J. Pettman, J. D. Smith,
Org. Process Res. Dev. 2008, 12, 575–583; p) R. R. Sri-
vastava, A. J. Zych, D. M. Jenkins, H. J. Wang, Z. J.
Chen, D. J. Fairfax, Synth. Commun. 2007, 37, 431–
2
4
4
38; q) P. Dolakova, M. Masojidkova, A. Holy, Hetero-
tion of the solvents the residue was subjected to column
chromatography (silica, hexane/ethyl acetate). All known
benzonitriles were identified by comparison with commer-
cially available materials and literature data.
cycles 2007, 71, 1107–1115; r) X. Wang, B. Zhi, J.
Baum, Y. Chen, R. Crockett, L. Huang, S. Eisenberg, J.
Ng, R. Larsen, M. Martinelli, P. Reider, J. Org. Chem.
2
006, 71, 4021–4023; s) M. T. Martin, B. Liu, B. E.
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[8]
2
557; cf. also ref.
6] a) T. Schareina, A. Zapf, M. Beller, Chem. Commun.
004, 1388–1389; b) T. Schareina, A. Zapf, M. Beller,
[
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[
1] Selected recent reviews of Pd-catalyzed coupling reac-
[
7] Other cyanation sources, for example, KCN [LD
Lo
tions see: a) A. Frisch, M. Beller, Angew. Chem. 2005,
À1
(
oral, human)=2.86 mgkg ], are highly poisonous,
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431–440; c) C. Barnard, Platinum Met. Rev. Platinum
K [Fe(CN) ] is essentially non-toxic {the LD of
4
6
50
K [Fe(CN) ] is lower than that for NaCl}.
4
6
K [Fe(CN) ]·3H O is used as an anti-agglutinating
4
6
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