Mild and Efficient Cobalt-Catalyzed Cross-Coupling of Aliphatic Amides and Aryl Iodides in Water

Article abstract of DOI:10.1055/s-0034-1380724

A convenient protocol for the C-N cross-coupling of aliphatic amides and iodobenzene is demonstrated using a simple and inexpensive Co(C₂O₄)·2H₂O/N,N′-dimethylethylenediamine (DMEDA) catalytic system in water. Good yields of N-arylated products were isolated (up to 85%) and the protocol has been successfully applied to the synthesis of the anticancer drug, flutamide.

Full text of DOI:10.1055/s-0034-1380724

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1697–1701
letter
1697
B. Y.-H. Tan, Y.-C. Teo
Letter
Synlett
Mild and Efficient Cobalt-Catalyzed Cross-Coupling of Aliphatic
Amides and Aryl Iodides in Water
Bryan Yong-Hao Tan
Yong-Chua Teo*
O
Co(C2O4)⋅2H2O (20 mol%)
O
R1
R2
Cs2CO3 (2 equiv)
R2
+
HN
R1
NH2
I
DMEDA (40 mol%)
H2O
Natural Sciences and Science Education, National Institute of
Education, Nanyang Technological University, 1 Nanyang Walk,
637616, Singapore
120–130 °C
24 h
up to 85 % yield
yongchua.teo@nie.edu.sg
Received: 02.04.2015
Accepted after revision: 14.04.2015
Published online: 01.06.2015
tocol that provides access to a broader scope of N-aryl ali-
phatic amides would represent a welcome advance in this
class of transformation.
DOI: 10.1055/s-0034-1380724; Art ID: st-2015-d0235-l
The application of cobalt salts to carbon–heteroatom
bond-formation reactions has recently attracted keen inter-
est and has provided a new synthetic methodology.13 Bene-
fits of using this alternative metal catalyst include its low
cost, stability, sustainability and environmentally benign
nature.14 In this aspect, we have recently demonstrated a
cobalt-catalyzed C–N arylation of benzamide and iodoben-
zene in aqueous medium.15 Given that excellent yields of up
to 92% were achieved for most substituted benzamides, we
envisaged the application of such a cobalt/ligand catalytic
system towards the more challenging cross-coupling of ali-
phatic amides and aryl halides. Herein, we report a versa-
tile, mild and practical cross-coupling of a wide range of
non-aromatic amides with iodobenzene in water. It is note-
worthy that the reaction does not require stringent inert
conditions and it proceeds efficiently in air.
Our initial study began with the application of the pre-
viously reported conditions for the cobalt-catalyzed N-ary-
lation15 towards the cross-coupling of iodobenzene and 2-
pyrrolidinone. To our delight, a modest yield of 50% of N-
arylated product was obtained (Table 1, entry 1). To im-
prove the yield, we hypothesized that a higher catalyst
loading could be utilized due to the lower reactivity of 2-
pyrrolidinone relative to benzamide. Indeed, a good yield of
75% was obtained through a slight increase of catalyst and
ligand loadings to 20 mol% and 40 mol% respectively (entry
2). Inspired by this result, we proceeded to examine the ef-
fects that different combinations of Co salts, base, ligands
and solvent had on the reaction. The results of this prelimi-
nary investigation are summarized in Table 1. Firstly,
amongst the Co(II) salts, Co(C2O4)·2H2O was found to be the
most effective at promoting the arylation process, affording
a good yield of 75%. All the other Co salts gave significantly
Abstract A convenient protocol for the C–N cross-coupling of aliphatic
amides and iodobenzene is demonstrated using a simple and inexpen-
sive Co(C2O4)·2H2O/N,N′-dimethylethylenediamine (DMEDA) catalytic
system in water. Good yields of N-arylated products were isolated (up
to 85%) and the protocol has been successfully applied to the synthesis
of the anticancer drug, flutamide.
Key words cobalt, N-arylation, cross-coupling, aliphatic amide, water
N-Aryl aliphatic amides are valuable moieties that are
frequently found in pharmaceutical and natural products.
They feature prominently in compounds used for the treat-
ment of hypertension,1 cancer,2 and for anaesthesia.3 This
class of organic molecules is readily synthesized through
the reaction of acyl chlorides with anilines. Although gen-
erally effective, this acylation approach is considered to be
less than desirable due to the possible genotoxicity of ani-
line and its impurities,4 while the lachrymatory property of
acyl chlorides also poses potential safety issues.5
Presented with these concerns, a straightforward and
appealing alternative for the synthesis of this moiety is the
metal-mediated C–N cross-coupling reaction between ali-
phatic amides and aryl halides. In this regard, protocols in-
volving the use of palladium6,7 and copper8,9 salts to cata-
lyze this class of transformation have emerged recently,
supplanting the classical Goldberg coupling reaction. How-
ever, in spite of the improvements made, one limitation still
persists; aromatic amides, which are typically more reac-
tive,10,11 are commonly employed as the nucleophile. There
is a consequent and associated lack in the substrate scope of
the less reactive aliphatic amides in these reported proto-
cols.7,8,12 Therefore, the development of an alternative pro-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1697–1701

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B. Y.-H. Tan, Y.-C. Teo
Letter
Synlett
lower yields (entries 3–6). The choice of Cs2CO3 as base was
found to be essential for efficient reaction; whereas other
bases such as K3PO4, K2CO3, Na2CO3 and C2H3O2Cs only af-
forded the N-arylated product in yields of less than 38%
(entries 7–10). Next, the efficiency of different diamine li-
gands on the reaction was examined (entries 11–14). N,N′-
Dimethylethylenediamine (DMEDA) was shown to be the
best ligand to form the active species with the cobalt cata-
lyst, when the desired product was isolated in 75% yield.
The solvent effect was subsequently probed through the
screening of a range of organic solvents and water proved to
be superior to all the organic solvents tested (entries 15–
20). Even polar organic solvents such as methanol and eth-
anol proved to be ineffective for this protocol. This result
points to the potential of this conversion in large-scale in-
dustrial applications.16
Next, control reactions were carried out in the absence
of Co salt or DMEDA (entries 22 and 23). Unsurprisingly,
traces of product and no reaction were observed, respec-
tively, verifying that both components are essential for the
success of the protocol. To conclude our optimization stud-
ies, a control reaction was carried out by applying Bolm’s
protocol of ppm copper-catalyzed N-arylation17 with our
Co salt. In his report, yields of 33–57% product were ob-
tained for the cross-coupling of iodobenzene and butan-
amide using ppm amounts of Cu salt. To our satisfaction,
only a trace amount of product was obtained when
Co(C2O4)·2H2O was applied to the same protocol, effectively
ruling out the possibility of catalysis due to Cu contami-
nants in our Co salt. In summary, the optimized conditions
for the C–N cross-coupling of iodobenzene and 2-pyrrolidi-
none involve Co(C2O4)·2H2O/DMEDA at 20 mol% and 40
mol%, respectively, Cs2CO3 as the base, at 120 °C for 24
hours in air.
In order to evaluate the generality of the protocol with
respect to the aryl halide, a range of substituted aryl and
heteroaryl iodides were reacted with 2-pyrrolidinone un-
der the optimized conditions. The results of this study are
shown in Table 2. In general, good yields of the correspond-
ing N-aryl amide derivatives were obtained (up to 85%).
Steric effects were significant, where bulky ortho substitu-
ents such as Cl and OMe groups tend to hamper the reac-
tion. However, encouraging yields of up to 52% could still be
obtained, albeit at slightly elevated temperature of 130 °C
(entries 3 and 4).
Interestingly, this trend was not observed for 2-fluoro-
iodobenzene, where a good yield of 73% was obtained (en-
try 2). This is possibly due to the less bulky nature and in-
ductive effect of the fluoro substituent. The reaction can
tolerate substituents of different electronic effects at the
meta and para positions, affording good yields (entries 5–
15). However, certain functional groups such as CN, OH and
NH2 groups were not tolerated in the protocol. It is note-
worthy that C–N cross-coupling reaction can also be carried
Table 1 Optimization Studies on the Co-Catalyzed Cross-Coupling of
Pyrrolidinone and Iodobenzenea
O
O
[Co] (20 mol%)
base (2 equiv)
+ I
N
NH
ligand (40 mol%)
solvent
120 °C, 24 h
ligand:
N
N
H2N
NH2
NH HN
L1
Entry Catalyst
NH2
H2N
HN
L5
NH
L2
L3
L4
Base
Ligand Solvent Yield (%)b
1
2
Co(C2O4)·2H2O
Co(C2O4)·2H2O
Co(OAc)2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L1
L1
L1
L1
L1
L1
L1
L1
-
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
MeOH
EtOH
DMF
DMSO
THF
50c
75
3
20
4
Co(ClO4)2·6H2O
CoCl2
42
5
50
6
Co(C5H7O2)2
37
7
Co(C2O4)·2H2O
Co(C2O4)·2H2O
Co(C2O4)·2H2O
Co(C2O4)·2H2O
Co(C2O4)·2H2O
Co(C2O4)·2H2O
Co(C2O4)·2H2O
Co(C2O4)·2H2O
Co(C2O4)·2H2O
Co(C2O4)·2H2O
Co(C2O4)·2H2O
Co(C2O4)·2H2O
Co(C2O4)·2H2O
Co(C2O4)·2H2O
Co(C2O4)·2H2O
-
38
8
K2CO3
30
9
Na2CO3
C2H3O2Cs
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
trace
trace
15
10
11
12
13
14
15
16
17
18
19
20
21
22
23
0
30
41
trace
trace
trace
trace
trace
toluene trace
H2O
H2O
H2O
25d
trace
0
Co(C2O4)·2H2O
a Reaction conditions: Co catalyst (20 mol%), base (2.94 mmol), pyrrolidi-
none (1.47 mmol), ligand (40 mol%), H2O (0.3 mL), iodobenzene (2.21
mmol), at 120 °C for 24 h in air.
b Isolated yield.
c The reaction was carried out using 10 mol% Co catalyst and 20 mol% li-
gand.
d The reaction was carried out at 110 °C.
out smoothly using heteroaryl iodides to afford good yields
of up to 60% (entries 16 and 17). Unfortunately, bromoben-
zene derivatives proved to be unsuitable electrophilic part-
ners for the reaction, where only 15% and trace amounts of
the desired product were isolated when the reaction was
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1697–1701

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B. Y.-H. Tan, Y.-C. Teo
Letter
Synlett
Table 2 N-Arylation of Pyrrolidinone with Various Substituted Aryl Ha-
yield from 40% to 68% could be observed when cyclopro-
panecarboxamide was replaced with cyclohexanecarbox-
amide as the nucleophilic partner (entries 7–9).
lidesa
Co(C2O4)⋅2H2O
(20 mol%)
O
O
Table 3 N-Arylation of Aliphatic Amides with Iodobenzenea
R
R
Cs2CO3 (2 equiv)
NH
+
N
I
DMEDA (40 mol%)
H2O
O
Co(C2O4)⋅2H2O (20 mol%)
O
R
Cs2CO3 (2 equiv)
120 °C, 24 h
I
HN
+
R
NH2
DMEDA (40 mol%)
H2O
Entry
ArX
PhI
Product
Yield (%)b
130 °C, 24 h
1
2
2a
2b
2c
2d
2e
2f
75
Entry
R
Product
Yield (%)b
2-FC6H4I
73
3
2-ClC6H4I
2-OMeC6H4I
3-FC6H4I
40c
50c
72
1
2
Me
3a
3b
3c
3d
3e
3f
trace
trace
60
4
Et
5
3
Pr
6
3-ClC6H4I
3-BrC6H4I
3-CF3C6H4I
3-OMeC6H4I
3-NO2C6H4I
4-FC6H4I
80
4
i-Pr
60
7
2g
2h
2i
85
5
Bu
64
8
72
6
pentyl
cyclopropyl
cyclopentyl
cyclohexyl
Bn
65
9
60
7
3g
3h
3i
40
10
11
12
13
14
15
16
17
18
19
2j
50
8
68
2k
2l
82
9
62
4-ClC6H4I
4-CF3C6H4I
4-OMeC6H4I
4-MeC6H4I
2-I-thiophene
3-I-thiophene
PhBr
60
10
3j
70
a Unless otherwise stated, the reaction was carried out with Co(C2O4)·2H2O
(20 mol%), Cs2CO3 (2.94 mmol), aliphatic amides (1.47 mmol), DMEDA (40
mol%), H2O (0.3 mL), iodobenzene (2.21 mmol), at 130 °C for 24 h in air.
b Isolated yield.
2m
2n
2o
2p
2q
2a
2r
71
60
60
60
This observation could possibly be due to the extra ste-
ric stability offered by substituents with bulkier alkyl
groups.10,18 2-Phenylethanamide, a substrate which con-
tained α-acidic protons, was well tolerated by the protocol,
affording the corresponding N-arylated amide in a good
yield of 70% (entry 10).
50
20c
tracec
4-FC6H4Br
a Unless otherwise stated, the reaction was carried out with Co(C2O4)·2H2O
(20 mol%), Cs2CO3 (2.94 mmol), 2-pyrrolidinone (1.47 mmol), DMEDA (40
mol%), H2O (0.3 mL), substituted iodobenzene (2.21 mmol), at 120 °C for
24 h in air.
To demonstrate the synthetic utility of this procedure,
we attempted to synthesize flutamide, a non-steroidal an-
tiandrogen used primarily to treat prostate cancer. Tradi-
tionally, flutamide is synthesized through the reaction of 4-
nitro-3-(trifluoromethyl)aniline and isobutyryl chloride.19
Recently, Bandgar and Sawant described a green, recyclable
method through the use of 2,4,6-trichloro-1,3,5-triazine
and N-methylmorpholine,20 while Ghaffarzadeh and Rah-
bar demonstrated the assembly of the C–N using 3-trifluo-
ronitrobenzene, in the presence of an Fe catalyst under re-
flux conditions.21 However, both protocols proved to be
more complex than the traditional method. In light of this,
we were able to synthesize flutamide using the Co-cata-
lyzed C–N cross-coupling of isobutyramide and 1-iodo-3-
(trifluoromethyl)benzene, followed by nitration20 of the re-
sultant 3-trifluoroisobutyranilide (Scheme 1). Through this
practical two-step synthesis, we were able to obtain flut-
amide in good yield.
b Isolated yield.
c The reaction was carried out at 130 °C.
carried out at slightly elevated temperature (entries 18 and
19).
Next, the substrate scope of the protocol was tested
with a range of aliphatic amides. As shown in Table 3, mod-
erate to good yields of up to 70% were obtained when the
reactions were conducted at 130 °C. To the best of our
knowledge, this protocol demonstrates the widest scope of
alkyl and cyclic amides as the N-nucleophile for a cross-
coupling reaction of this type. Of the amides screened, reac-
tions using ethanamide and propanamide proved to be un-
successful (Table 3, entries 1 and 2). Nevertheless, good
yields of up to 65% were obtained for amides with alkyl
substituents of more than two carbons (entries 4–6). Simi-
larly, this trend was observed when amides with cycloalkyl
rings as substituents were employed. An increase in the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1697–1701

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B. Y.-H. Tan, Y.-C. Teo
Letter
Synlett
In summary, a mild, simple and efficient method for the
CF3
CF3
C–N cross-coupling
O
preparation of N-aryl aliphatic amides via Co-catalyzed
cross-coupling reaction in water has been developed.23 Fur-
thermore, a good range of substrates can be used in the pro-
tocol, complementing previously reported cross-coupling
reactions. We also succeeded in applying our optimized
conditions to the synthesis of flutamide. Studies to expand
the scope of cobalt-catalyzed cross-coupling reactions are
currently ongoing.
reaction
O
+
I
NH2
N
H
key intermediate
4a: 60%
concd HNO3/concd H2SO4
4 h
CF3
Acknowledgment
NO2
O
We would like to thank the National Institute of Education and
Nanyang Technological University (RP 5/13 TYC) for funding this
work.
N
H
flutamide
65%
Supporting Information
Scheme 1 Synthesis of flutamide via a C–N cross-coupling
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380724.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
The utility of our approach was further illustrated with
the synthesis of a range of intermediates that could be ni-
trated to yield flutamide derivatives (Scheme 2, compounds
4a–f). In general, good yields of up to 75% were obtained
using the optimized conditions. Given that certain flut-
amide analogues with modifications of the aliphatic side
chain showed antiandrogen and antiprogestin properties,22
this cross-coupling method could potentially be a mild and
convenient method of accessing such structures.
References and Notes
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Co(C2O4)⋅2H2O
CF3
O
CF3
(20 mol%)
O
R
Cs2CO3 (2 equiv)
+
I
HN
R
NH2
DMEDA (40 mol%)
H2O
130 °C, 24 h
CF3
CF3
CF3
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O
O
O
N
(C4H9)
N
H
(C5H11
)
N
H
H
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4a: 60%
4b: 60%
4c: 56%
CF3
CF3
CF3
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Mitra, R.; Saha, P.; Punniyamurthy, T. J. Org. Chem. 2009, 74,
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O
O
O
N
N
H
N
H
H
4d: 75%
4e: 60%
4f: 55%
Scheme 2 Synthesis of intermediates of flutamide derivatives. Isolated
yields are given for reactions carried out with Co(C2O4)·2H2O (20 mol%),
Cs2CO3 (2.94 mmol), aliphatic amide (1.47 mmol), DMEDA (40 mol%),
H2O (0.3 mL), 1-iodo-3-(trifluoromethyl)benzene (2.21 mmol), at 130
°C for 24 h in air.
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Letter
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1-Phenylpyrrolidin-2-one (2a): off-white solid; 176 mg (75%
yield). 1H NMR (400 MHz, CDCl3): δ = 7.61 (d, J = 7.7 Hz, 2 H),
7.38 (t, J = 8.0 Hz, 2 H), 7.15 (t, J = 8.0 Hz, 1 H), 3.88 (t, J = 7.0 Hz,
2 H), 2.62 (t, J = 8.0 Hz, 2 H), 2.17 (quin, J = 8.2 Hz, 2 H). 13C NMR
(100 MHz, CDCl3): δ = 182.0, 136.5, 128.9, 124.5, 120.0, 48.8,
32.8, 18.1. HRMS: m/z [M+] calcd for C10H11NO: 162.0917;
found: 162.0914.
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1-(2-Fluorophenyl)pyrrolidin-2-one (2b): off-white solid; 192
1
mg (73% yield). H NMR (400 MHz, CDCl3): δ = 7.38–7.43 (m, 1
H), 7.21–7.28 (m, 1 H), 7.10–7.18 (m, 2 H), 3.83 (t, J = 6.8 Hz, 2
H), 2.57 (t, J = 8.4 Hz, 2 H), 2.21 (qn, J = 7.6 Hz, 2 H). 13C NMR
(100 MHz, CDCl3): δ = 174.7, 157.0 (d, J = 248.4 Hz), 128.2 (d, J =
7.6 Hz), 127.8 (d, J = 2.3 Hz), 126.3 (d, J = 11.4 Hz), 124.4 (d, J =
3.8 Hz), 116.5 (d, J = 19.8 Hz), 49.9, 31.0, 18.9. HRMS: m/z [M+]
calcd for C10H10NOF: 180.0822.; found: 180.0806.
(20) Bandgar, B.; Sawant, S. Synth. Commun. 2006, 36, 859.
(21) Ghaffarzadeh, M.; Rahbar, S. J. Chem. Res. 2014, 38, 200.
(22) (a) Dukes, M.; Furr, B. J.; Hughes, L. R.; Tucker, H.; Woodburn, J.
R. Steroids 2000, 65, 725. (b) Labrie, F. Cancer 1993, 72, 3816.
(23) General Procedure for N-Arylation of Pyrrolidinone/Ali-
1-(3-Methoxyphenyl)pyrrolidin-2-one (2i): pale yellow solid;
169 mg (60% yield). 1H NMR (400 MHz, CDCl3): δ = 7.33 (t, J = 2.8
Hz, 1 H), 7.24 (t, J = 8.0 Hz, 1 H), 7.10 (dd, J = 8.0 Hz, 1 H), 6.70
(dd, J = 8.0 Hz, 1 H), 3.82 (t, J = 8.0 Hz, 2 H), 3.80 (s, 3 H), 2.58 (t,
J = 8.0 Hz, 2 H), 2.12 (qn, J = 7.2 Hz, 2 H). 13C NMR (100 MHz,
CDCl3): δ = 174.2, 159.9, 140.6, 129.4, 111.9, 110.0, 105.9, 55.2,
48.8, 32.8, 17.9. HRMS: m/z [M+] calcd for C11H13NO2: 192.1022;
found: 192.1011.
N-[3-(Trifluoromethyl)phenyl]pentanamide (4b): off-white
solid; 216 mg (60% yield). 1H NMR (400 MHz, CDCl3): δ = 7.81 (s,
1 H), 7.72 (d, J = 9.2 Hz, 1 H), 7.66 (br s, 1 H), 7.40 (t, J = 8.8 Hz, 1
H), 7.34 (d, J = 8.8 Hz, 1 H), 2.38 (t, J = 8.0 Hz, 2 H), 1.70 (qn, J =
8.0 Hz, 2 H), 1.34–1.44 (m, 2 H), 0.93 (t, J = 7.6 Hz, 3 H). 13C NMR
(100 MHz, CDCl3): δ = 172.0, 138.5, 131.3 (q, J = 32.8 Hz), 129.5,
123.9 (q, J = 270.6 Hz), 122.9, 120.7 (q, J = 3.4 Hz), 116.6 (q, J =
3.5 Hz), 47.4, 37.6, 22.3, 13.8. HRMS: m/z [M+] calcd for
phatic Amides:
A mixture of cobalt(II) oxalate dihydrate
(Sigma-Aldrich, 0.294 mmol), Cs2CO3 (2.94 mmol), pyrrolidi-
none or aliphatic amide (1.47 mmol), DMEDA (0.588 mmol),
distilled H2O (0.3 mL) and aryl halide (2.205 mmol) were added
to an 8.0-mL reaction vial fitted with a Teflon-sealed screw cap.
The reaction mixture was stirred under air in a closed system at
120 °C and 130 °C, respectively for 24 h. The heterogeneous
mixture was subsequently cooled to r.t. and diluted with
CH2Cl2. The combined organic extracts were dried over anhyd
Na2SO4, filtered and the solvent was removed under reduced
pressure. The crude product was loaded into the column using
minimal amounts of CH2Cl2 and was purified by silica gel
C
12H14NOF3: 246.1103; found: 246.1117.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1697–1701