Efficient cross-coupling reactions of nitrogen nucleophiles with aryl halides in water

Article abstract of DOI:10.1002/adsc.200800746

A facile and practical strategy has been developed for the N-arylation of nitrogen nucleophiles with aryl halides catalyzed by a combination of iron(III) chloride [FeCl₃] and dimethylethylenediamine (dmeda) in water. A variety of nitrogen nucleophiles including pyrazole, indole, 7-azaindole and benzamide afforded the N-arylated products in the presence of the catalytic system (in up to 88% yield).

Full text of DOI:10.1002/adsc.200800746

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DOI: 10.1002/adsc.200800746
Efficient Cross-Coupling Reactions of Nitrogen Nucleophiles with
Aryl Halides in Water
a,
Yong-Chua Teo *
a
Natural Sciences and Science Education, National Institute of Education, Nanyang Technological University, 1 Nanyang
Walk, Singapore 637616
Fax : (+65)-6896-9414; phone: (+65)-6790-3846; e-mail: yongchua.teo@nie.edu.sg
Received: December 2, 2008; Revised: February 26, 2009; Published online: March 17, 2009
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A facile and practical strategy has been
developed for the N-arylation of nitrogen nucleo-
philes with aryl halides catalyzed by a combination
avoids the problems of pollution that are inherent
[
6]
with organic solvents. The synthesis of organic mole-
cules via reactions in water is an extensively investi-
gated topic which entails the additional challenges of
of iron ACHTUNGTRENNUNG( III) chloride [FeCl ] and dimethylethylene-
3
[
7]
diamine (dmeda) in water. A variety of nitrogen nu-
cleophiles including pyrazole, indole, 7-azaindole
and benzamide afforded the N-arylated products in
the presence of the catalytic system (in up to 88%
yield).
water tolerance for the catalyst and the associated
problem of substrate solubilities and reactivities. In
this aspect, the development of direct metal-catalyzed
coupling reactions that utilize less expensive and
more sustainable catalysts in water remains an elusive
goal in modern synthetic chemistry. The majority of
recent strategies for the transition metal-mediated
coupling reactions in aqueous media has been pro-
Keywords: arylation; cross-coupling; heterogeneous
catalysis; iron; water
[8]
moted either by palladium or copper metal catalysts.
To the best of our knowledge, the utilization of iron
catalysts for coupling reactions in water has yet to be
reported. In this paper, we disclose the first N-aryla-
The transition metal-catalyzed formation of carbon/ tion of nitrogen heterocycles with aryl halides cata-
heteratom bonds has recently experienced a renais- lyzed by a combination of readily available FeCl with
3
sance in chemical synthesis and emerged as a versatile chelating diamine derivatives in water.
tool for the synthesis of important intermediates in
The iron-catalyzed N-arylation of nitrogen nucleo-
[
1]
the pharmaceutical and fine chemical industries. In philes attracted our attention because of our endeav-
particular, the N-arylation of nitrogen heterocycles ours towards the development of environmentally
with aryl halides has acquired a major role due to the friendly protocols and the need for a more versatile
versatility of the products, which are prevalent build- and operational simple catalytic system for this impor-
ing blocks for the construction of many natural prod- tant process which avoids the use of organic solvents
ucts and medicinal agents. The vast majority of the and stringent inert conditions for the reaction. In our
existing protocols for performing this type of transfor- initial study, the reaction between iodobenzene 1 and
mation has been mediated by palladium and copper 1H-pyrazole 2 was chosen as model for the coupling
[2]
metal catalysts. Recently, the use of iron salts to per- reaction in water. A series of experiments was carried
form established transition metal-catalyzed coupling out to evaluate the ability of various ligands and iron
reactions has also emerged as an alternative and sources for the N-arylation process. The standardized
[
3,4]
promising strategy
following the pioneering work protocol was carried out using 1H-pyrazole (1 equiv.),
[5]
by Tamura and Kochi. Iron salts are inexpensive, iodobenzene (1.5 equiv.), iron source (20 mol%),
relatively less toxic and, in consequence more envi- ligand (40 mol%), tripotassium phosphate monohy-
ronmentally benign in comparison to other transition drate K PO ·H O (2 equiv.) in water at 1258C for
3
4
2
metals.
Organic reactions in water have recently attracted
24 h. The optimization results are shown in Table 1.
Investigation into the ligand system revealed that
much attention too, not only because unique reactivi- the reaction proceeded in a biphasic system with the
ty is often observed in water but also due to its low best yield achieved when the reaction was carried out
cost, safety and environmentally benign nature which using a combination of FeCl and N,N’-dimethylethy-
3
720
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Efficient Cross-Coupling Reactions of Nitrogen Nucleophiles with Aryl Halides in Water
COMMUNICATIONS
Table 1. Screening of various ligands and iron sources for spectively (Table 1, entries 6 and 9). Conversely, the
[a]
the N-arylation of pyrazole 2 in water.
employment of [Fe
ACTHUNGTRENNUN(G acac) ], Fe AHCTUNGTRENNNUG( oxalate)·2H O and
2
2
Fe O as the iron source afforded the products in
2
3
lower yields of 64%, 52% and 41%, respectively
Table 1, entries 11 and 12). In summary, the optimal
(
conditions for the N-arylation process in water consist
of the combination of FeCl (10 mol%), dmeda L4
3
(
20 mol%) and K PO ·H O (2 equiv.) at 1258C for
3 4 2
36 h.
With a set of optimized conditions in hand, a study
was initiated to explore the scope of the aryl halides
in the NÀH arylation process. We carried out the re-
actions using 1H-pyrazole as the nitrogen nucleophile
and a variety of substituted aryl iodides and bromides
under the optimized reaction conditions. The results
obtained are shown in Table 2.
[b]
Entry
Fe source
Ligand
Yield [%]
In general, the reaction of 1H-pyrazole with aryl io-
dides provided much superior yields than those with
aryl bromides employed as arylating agents. The
steric effect of ortho-substituents on the aryl iodides
was highly significant as the reactions led to lower
yields of the arylated products regardless of the elec-
tronic nature of the substituents (Table 2, entries 2
and 3). In this context, the protocol was limited only
to sterically unhindered aryl halides. The reaction was
highly chemoselective, reacting only between the
carbon atom and the iodine substituent even in the
presence of other halogen substituents (Table 2, en-
tries 3, 5, 7, 8 and 9). The reaction occurs only at the
iodo substituent when 4-fluoro-, 4-chloro- and 4-bro-
moiodobenzene were used as the electrophilic coun-
terparts. Moreover, the system was also efficient
when substituted 3-methylpyrazole was used as the
nucleophilic counterpart, affording the arylated prod-
uct in a good yield of 73% (entry 13). It is worthy of
note that the reaction was operationally simple and
convenient to carry out in a screw-capped reaction
1
2
3
4
5
6
7
8
9
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
L1
L2
L3
L4
L5
L4
none
L4
L4
L4
L4
L4
trace
0
58
72
trace
[c]
FeCl3
76
0
FeCl3
none
0
Fe
[Fe
Fe(oxalate) ·2H O
Fe O3
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(ClO )
74
64
52
41
4
2
10
11
12
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
ACHTUNGTRENNUNG( acac) ]
2
ACHTUNGTRENNUNG
2
2
2
[
a]
Unless otherwise noted, the reaction was carried out
with 1H-pyrazole (2.16 mmol), iodobenzene (3.24 mmol),
K PO ·H O (4.32 mmol), Fe source (20 mol%), ligand
3
4
2
(
40 mol%) in water (1.5 mL) at 1258C for 24 h.
Isolated yield after column chromatography.
The reaction was performed with Fe source (10 mol%)
and L4 (20 mol%) in water (1.5 mL) at 1258C for 36 h.
[
[
b]
c]
lenediamine (dmeda) L4 (Table 1, entry 4). Moderate vial, which precludes the need for stringent inert con-
yield was also achieved when trans-1,2-diaminocyclo- ditions and use of sealed apparatus as compared to
hexane L3 (Table 1, entry 3) was employed as the as- previous reports on iron-catalyzed cross-coupling re-
sisting ligand. However, only a trace amount of the actions. Moreover, the employment of water as the
product was detected in both cases of l-proline L1 sole reaction media and FeCl being an inexpensive
3
and N,N,N’,N’-tetramethylethylene diamine (tmeda) and environmentally benign metal species (other iron
L5 as ligands (Table 1, entries 1 and 5). It is worthy of salts are more expensive than FeCl ) greatly enhances
3
note that the reaction was found to proceed with the economical and environmentally friendly aspects
good yield when the amount of FeCl was reduced to of this catalytic system.
3
10 mol% albeit with extended reaction times (Table 1,
The scope of the arylation was tested with other
entry 6). Control experiments were also carried out to heterocycles and both acyclic and cyclic amides. The
confirm that no product was obtained in the absence results are shown in Table 3. Heterocycles such as
of either the ligand or iron source (Table 1, entries 7 indole and 7-azaindole were found to be effective nu-
and 8). With this encouraging result, we proceed to cleophilic counterparts for the coupling process, af-
screen the efficiency of the various iron sources for fording the respective N-phenyl derivatives (Table 3,
the N-arylation process using 10 mol% iron catalyst entries 1–4) in good yields (up to 81%) although with
loading and 20 mol% dmeda L4 in water. Among a slightly higher catalyst loading. Moreover, the N-ar-
them, the reaction catalyzed by either FeCl3 or ylation of benzamide was also accomplished in mod-
Fe
ACHTUNGTRENNUNG( ClO ) in combination with L4 afforded the N-ary- erate yields (Table 3, entries 5 and 6) under the influ-
4 2
lated products in good yields of 76% and 74%, re- ence of the catalytic system. However, the reactions
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Yong-Chua Teo
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Table 2. N-Arylation of pyrazole 2 with aryl halides cata-
Table 3. N-Arylation of indole, 7-azaindole, benzamide and
[a]
lyzed by FeCl /dmeda in water.
pyrrolidin-2-one with aryl halides catalyzed by FeCl /dmeda
3
3
[a]
in water.
[b]
Entry ArX
1
Product
Yield [%]
3a 76
[b]
Entry NuH
1
Product
Yield [%]
4a 61
2
3
3b 45
3c 17
2
3
4
5
4b 40
5a 81
5b 78
6a 46
4
5
3d 74
3e 75
6
7
8
9
3f 88
3g 80
3h 70
6
7
6b 55
7a 25
3i
75
8
9
7b 12
1
0
3a 23
8
9
trace
trace
1
1
1
1
2
3
3j
32
1
1
0
1
3f 21
3k 73
10 trace
[c]
[
a]
[
a]
Unless otherwise noted, the reaction was carried out
with nitrogen nucleophile (2.16 mmol), aryl halide
Unless otherwise noted, the reaction was carried out
with 1H-pyrazole (2.16 mmol), aryl halide (3.24 mmol),
K PO ·H O (4.32 mmol), FeCl3 (10 mol%), dmeda
(
3.24 mmol), K PO ·H O (4.32 mmol), FeCl (20 mol%),
3 4 2 3
3
4
2
dmeda (40 mol%) in water (1.5 mL) at 1258C for 36 h.
Isolated yield after column chromatography.
(20 mol%) in water (1.5 mL) at 1258C for 36 h.
[b]
[
[
b]
c]
Isolated yield after column chromatography.
3-Methylpyrazole was used as the nucleophilic counter-
part in the reaction.
Based on literature reports, a possible mechanism
of the iron-catalyzed cross-coupling is proposed in
were less satisfactory in the case of cyclic amides Scheme 1. The mechanism involves three elementary
Table 3, entries 7 and 8) and only trace amounts of steps: coordination of the nitrogen nucleophile to the
the desired products were detected when imidazole iron(II)-dmeda complex, oxidative addition of the
Table 3, entry 9), aromatic (Table 3, entry 10) and aryl halide, and reductive elimination of the coupling
alkyl amines (Table 3, entry 11) were employed. product, thereby regenerating the active catalytic spe-
(
(
722
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Efficient Cross-Coupling Reactions of Nitrogen Nucleophiles with Aryl Halides in Water
COMMUNICATIONS
resulting solution was directly filtered through a pad of
celite and washed with saturated NaCl. The combined or-
ganic extracts were dried with anhydrous MgSO and the
4
solvent removed under reduced pressure. The crude product
was purified by silica-gel column chromatography to afford
the N-arylated product. The identity and purity of known
1
13
products was confirmed by H and C NMR spectroscopic
analysis. See the supporting information for full details.
Acknowledgements
The author would like to thank the National Institute of Edu-
cation, Nanyang Technological University (Grant No. RP5/06
TYC) for their generous support.
Scheme 1. Proposed mechanism of the iron-catalyzed N-ary-
lation of nitrogen nucleophiles.
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Adv. Synth. Catal. 2009, 351, 720 – 724
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