Efficient copper-catalyzed coupling of 2-haloacetanilides with phosphine oxides and phosphites under mild conditions

Article abstract of DOI:10.1055/s-0028-1083155

We have developed a highly efficient method for the copper-catalyzed coupling of 2-haloacetanilides with phosphine oxides and phosphites in the presence of a catalytic amount of copper(I) iodide and N-methylpyrrolidine-2- carboxamide under mild conditions (45-55°C); the P-arylation products were synthesized in good to excellent yields in short times using 2-bromotrifluoroacetanilides and 2-iodotrifluoroacetanilides as the starting materials. This represents the lowest reaction temperatures for copper-catalyzed P-arylation thus far. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083155

PAPER
3473
Efficient Copper-Catalyzed Coupling of 2-Haloacetanilides with Phosphine
Oxides and Phosphites under Mild Conditions
C
opper-Catalyzed
e
Coupling
o
s
f
2-Haloa
h
cetanilide
s
w
o
ith Phosphor
u
us Compounds Jiang,a Qun Jiang,b Hua Fu,*a Yuyang Jiang,a,b Yufen Zhaoa
a
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, P. R. of China
Fax +86(10)62781695; E-mail: fuhua@mail.tsinghua.edu.cn
Key Laboratory of Chemical Biology (Guangdong Province), Graduate School of Shenzhen, Tsinghua University, Shenzhen 518057,
P. R. of China
b
Received 14 May 2008; revised 2 July 2008
conditions8 and avoid the formation of benzoxazoles at
higher temperature,9 hence we initially transformed 2-ha-
loanilines into 2-halotrifluoroacetanilides. We also opti-
mized the catalysis conditions, including copper source,
Abstract: We have developed a highly efficient method for the
copper-catalyzed coupling of 2-haloacetanilides with phosphine
oxides and phosphites in the presence of a catalytic amount of cop-
per(I) iodide and N-methylpyrrolidine-2-carboxamide under mild
conditions (45–55 °C); the P-arylation products were synthesized in ligand, base, solvent, and amount of catalyst and ligand, in
good to excellent yields in short times using 2-bromotrifluoroacet-
order to achieve good coupling yields of aryl halides with
anilides and 2-iodotrifluoroacetanilides as the starting materials.
organophosphorus compounds containing P–H (Table 1).
This represents the lowest reaction temperatures for copper-cata-
lyzed P-arylation thus far.
Several ligands, N,N¢-dimethylethylenediamine (A,
Table 1, entry 1),10 amino acids B–E (Table 1, entries 2–
5),11 rac-BINOL F (Table 1, entry 6),12 N-methylpyrroli-
dine-2-carboxamide (G, Table 1, entry 7),13 were tested
with 2-bromotrifluoroacetanilide and diphenylphosphine
oxide used as model substrates. The results showed that
N-methylpyrrolidine-2-carboxamide (G) exhibited the
best activity. We also studied the effect of solvents (cf.
Table 1, entries 7, 9–11); 1,4-dioxane and N,N-dimethyl-
formamide provided better yields, but toluene was a poor
solvent. The base also influenced the reaction rate; cesium
carbonate gave the highest yield (Table 1, entry 7), by
comparison sodium carbonate (Table 1, entry 12), potas-
sium phosphate (Table 1, entry 13), and potassium car-
bonate (Table 1, entry 14) provided lower yields. The
copper sources were also investigated (cf. Table 1, entries
7, 15–18) and the results show that copper(I) iodide was
the best catalyst. The reaction yield improved as increas-
ing amounts of copper(I) iodide and N-methylpyrrolidine-
2-carboxamide (G) were used. The coupling yield greatly
decreased (<35%) when the ortho-NHCOCF3 in 2-halo-
trifluoroacetanilides was replace with an ortho-NHCOMe
group. After optimization of the ligand, solvent, base, and
catalyst, the cross-coupling reactions were carried out un-
der our standard conditions, 30 mol% copper(I) iodide as
the catalyst, 100 mol% N-methylpyrrolidine-2-carboxam-
ide as the ligand relative to the aryl halide, anhydrous 1,4-
dioxane as the solvent, and 1.5 equivalents of cesium car-
bonate as the base.
Key words: Ullmann reaction, P-arylation, ortho effect, copper
catalysis, N,N-ligand
Many efficient arylphosphine ligands with diverse struc-
tures have been developed and utilized extensively in both
academic research and industry.1 Aryl- and vinylphospho-
nic acid moieties are key functionalities in many biologi-
cally active compounds,2 and flame retardants.3 Although
many approaches to these compounds have been reported,
the direct coupling of aryl halides with P–H bonds is the
most straightforward strategy and palladium-catalyzed
P-arylation reactions are popular.4 Recently, several ex-
amples involving copper-catalyzed P-arylations have
been reported by us5a,b and other groups,5c–f but only aryl
iodides are good substrates; aryl bromides show weak re-
activity. In addition, the copper-catalyzed coupling usual-
ly requires aggressive reagents or rather harsh conditions,
such as higher heating temperatures (more than 100 °C)
and long reaction times (>10 h). Since o-aminoaryl-
phosphines6 and o-aminoarylphosphonates7 have been
used as the ligands for asymmetric synthesis and biologi-
cal active molecules, respectively, it is highly desired to
develop more convenient and economic synthetic routes.
Herein, we report a mild and highly efficient method for
the copper-catalyzed P-arylation of phosphine oxides and
phosphites catalyzed by copper(I) iodide/N-methylpyrrol-
idine-2-carboxamide.
As shown in Table 2, aryl bromides and iodides 1 (X = Br
or I) gave the products 3 in good to excellent yields and
aryl iodides displayed slightly higher activity than aryl
bromides. The aryl chloride 1 (X = Cl) was a weak sub-
strate, but it also provided a moderate yield (50%) of 3a
when the reaction temperature was raised to 110 °C
(Table 2, entry 3). Phosphites were better substrates than
phosphine oxides. The addition of electron-donating
groups to the 2-halotrifluoroacetanilides improved P-ary-
The ortho-NHCOCF3 in 2-halotrifluoroacetanilides could
promote copper-catalyzed Ullmann-type biaryl formation
and the enantioselective arylation of 2-methylacetoace-
tates in the presence of suitable ligands under mild
SYNTHESIS 2008, No. 21, pp 3473–3477
x
x.
x
x
.
2
0
0
8
Advanced online publication: 25.09.2008
DOI: 10.1055/s-0028-1083155; Art ID: F10708SS
© Georg Thieme Verlag Stuttgart · New York

3474
D. Jiang et al.
PAPER
Table 1 Copper-Catalyzed P-Arylation; Optimization of the Cata-
lation of the substrates and inhibited the formation of the
reduced products (debromination); completion of P-aryla-
tion needed longer times for aryl halides containing elec-
tron-withdrawing groups. We also investigated the ortho
effect of halotrifluoroacetanilides, the reactions selective-
ly occurred at the ortho site for 2,4-dibromotrifluoroacet-
anilide (Table 2, entries 8, 9). We attempted the coupling
of 3-bromotrifluoroacetanilide or 4-bromotrifluoroacet-
anilide with diphenylphosphine oxide at 50 °C under our
standard conditions, however, only trace amounts of
P-arylation products were observed. Reaction of 2,4-di-
bromotrifluoroacetanilide with diphenylphosphine oxide
(Table 2, entry 8) or diisopropyl phosphite (Table 2, entry
9) provided the monosubstituted products 3d and 3e.
These results show that the ortho-NHCOCF3 group in
2-halotrifluoroacetanilides could promote P-arylation.
lytic Conditionsa
O
O
NH
P
CF3
cat., ligand
base, solvent
NH
Br
CF3
O
P
Ph
Ph
Ph
Ph
+
H
50 °C, 5 h
H2O
COOH
Me
ligand = Me NH HN Me
COOH
N
N
A
B
H
C
Me
HO
COOH
N
COOH
N
H
D
H
E
NHMe
O
OH
OH
In summary, we have developed a highly efficient method
for the synthesis of [2-(trifluoroacetamido)aryl]phosphine
oxides and 2-(trifluoroacetamido)arylphosphonates using
inexpensive copper(I) iodide/N-methylpyrrolidine-2-car-
boxamide as the catalyst. Various substituted 2-halotri-
fluoroacetanilides were used as the substrate and the
coupling reactions were complete in short times under
mild conditions (45–55 °C). This method is of wide appli-
cation for the synthesis of diverse o-aminoarylphosphine
oxides, o-aminoarylphosphines, and o-aminoarylphos-
phonates.
N
H
G
F
Entry Catalyst Ligand Base
Solvent
Yieldb (%)
1
2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuSO4
A
B
C
D
E
F
Cs2CO3
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
DMSO
23
21
54
61
56
37
78
0c
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K3PO4
3
4
5
All reactions were carried out under an N2 atmosphere. DMF was
dried over CaH2 and freshly distilled before use. 1H and 13C NMR
spectra were recorded in CDCl3 with TMS as the internal standard
(1H NMR: TMS d = 0.00, CDCl3 d = 7.24; 13C NMR: CDCl3 d =
77.0).
6
7
G
–
8
Synthesis of (S)-N-Methylpyrrolidine-2-carboxamide
(S)-N-Methylpyrrolidine-2-carboxamide was prepared according to
the reported procedure.13
9
G
G
G
G
G
G
G
68
72
0
10
11
12
13
14
15
16
17
18
DMF
Synthesis of 3a–j; General Procedure
toluene
A flask was charged with CuI (57 mg, 0.3 mmol), N-methylpyrroli-
dine-2-carboxamide (128 mg, 1 mmol), Cs2CO3 (489 mg, 1.5
mmol), halotrifluoroacetanilide (1 mmol), phosphine oxide or phos-
phite (1.5 mmol), and 1,4-dioxane (2 mL). The flask was sealed and
the mixture was allowed to stir under N2 at the indicated tempera-
ture and time (Tables 1 and 2). When the coupling reaction was
complete (TLC), the mixture was diluted with EtOAc, the soln was
filtered, and the inorganic salts were removed. The solvent of the
filtrate was removed with the aid of a rotary evaporator and the res-
idue was purified by flash column chromatography (silica gel, PE–
EtOAc, 10:1 to 2:1) to provide the desired product.
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
35
49
46
0
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cu(OAc)2G
0
CuCl2
CuBr
G
35
65
G
Diphenyl[2-(trifluoroacetamido)phenyl]phosphine Oxide (3a)
White solid; yield: 80% (X = I); 78% (X = Br); 50% (X = Cl); mp
120–121 °C.
1H NMR (300 MHz, CDCl3): d = 12.64 (s, 1 H), 8.55–8.58 (m, 1 H),
7.47–7.65 (m, 11 H), 7.08–7.21 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 155.4 (q, J = 37.2 Hz), 142.2,
133.7, 133.1, 132.9, 132.2, 132.0, 131.5, 130.1, 129.0, 124.8, 124.6,
122.3, 117.8 (m).
a Reagents and conditions: 2-bromotrifluoroacetanilide (1.0 mmol),
Ph2PHO (1.5 mmol), catalyst (0.3 mmol), ligand (1 mmol), base (1.5
mmol), solvent (2 mL) under N2.
b Isolated yield.
c In the absence of ligand.
31P NMR (121 MHz, CDCl3): d = 38.01.
Synthesis 2008, No. 21, 3473–3477 © Thieme Stuttgart · New York

PAPER
Copper-Catalyzed Coupling of 2-Haloacetanilides with Phosphorus Compounds
3475
Table 2 N-Methylpyrrolidine-2-carboxamide-Promoted Copper-Catalyzed Coupling of Aryl Halides with Organophosphorus Compounds
Containing P–Ha
O
O
O
P
H
R2
R1
NH
CF3
30 mol % CuI
100 mol % L
R2
R1
NH
X
CF3
R3
R3
+
R3
R3
1,4-dioxane
Cs2CO3
3
1
P
O
2
NHMe
O
L =
N
H
Entry
R1
R2
R3
X
Temp (°C)/
Time (h)
Product
Yieldb (%)
1
2
H
H
H
H
H
H
H
Br
Br
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Br
I
50/5
3a
3a
3a
3b
3b
3c
3c
3d
3e
3f
78
80
50
93
92
90
91
84
72
78
91
92
56
87
Ph
50/4
3
Ph
Cl
Br
I
110/10
45/4
4
Oi-Pr
Oi-Pr
OBu
OBu
Ph
5
45/1.5
45/2
6
Br
I
7
45/1.5
50/6
8
Br
Br
Br
Br
Br
Br
Br
9
Oi-Pr
Ph
45/3
10
11
12
13
14
Me
Me
Me
H
50/10
45/3.5
45/4.5
55/48
50/10
OBu
Oi-Pr
OBu
Oi-Pr
3g
3h
3i
NO2
NO2
H
3j
a Reagents and conditions: aryl halide (1.0 mmol), phosphine oxide or phosphite (1.5 mmol), CuI (0.3 mmol), ligand G (1 mmol), Cs2CO3 (1.5
mmol), 1,4-dioxane (2 mL) under N2.
b Isolated yield.
HRMS: m/z [M + H]+ calcd for C20H16F3NO2P: 390.0871; found:
390.0875.
13C NMR (75 MHz, CDCl3): d = 155.6 (q, J = 36.8 Hz), 140.3,
134.3, 132.7, 129.2, 121.2, 120.9, 118.7 (m), 66.7, 32.3, 18.6, 13.5.
31P NMR (121 MHz, CDCl3): d = 19.30.
HRMS: m/z [M + H]+ calcd for C16H24F3NO4P: 382.1395; found:
Diisopropyl 2-(Trifluoroacetamido)phenylphosphonate (3b)
White oil; yield: 92% (X = I); 93% (X = Br).
1H NMR (300 MHz, CDCl3): d = 11.96 (s, 1 H), 8.54 (t, J = 7.50 Hz,
1 H), 7.53–7.63 (m, 2 H), 7.23 (t, J = 1.38 Hz, 1 H), 4.62–4.67 (m,
2 H), 1.36 (d, J = 6.18 Hz, 6 H), 1.25 (d, J = 6.18 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 155.3 (q, J = 37.3 Hz), 139.9,
139.8, 132.9, 129.2, 121.1, 120.9, 119.6 (m), 72.3, 23.9.
31P NMR (121 MHz, CDCl3): d = 15.08.
382.1393.
[5-Bromo-2-(trifluoroacetamido)phenyl]diphenylphosphine
Oxide (3d)
White solid; yield: 84%; mp 125–127 °C.
1H NMR (300 MHz, CDCl3): d = 8.45–8.48 (m, 1 H), 7.52–7.67 (m,
11 H), 7.13–7.21 (dd, J = 7.21 Hz, 1 H).
HRMS: m/z [M + H]+ calcd for C14H20F3NO4P: 354.1082; found:
354.1089.
13C NMR (75 MHz, CDCl3): d = 155.5 (q, J = 38.0 Hz), 141.1,
136.5, 135.2, 135.1, 135.0, 133.3, 132.3, 132.2, 132.0, 130.6, 129.3,
129.2, 124.0 (m).
Dibutyl 2-(Trifluoroacetamido)phenylphosphonate (3c)
Colorless oil; yield: 91% (X = I); 90% (X = Br).
1H NMR (300 MHz, CDCl3): d = 11.91 (s, 1 H), 8.56 (t, J = 6.51 Hz,
1 H), 7.57–7.65 (m, 2 H), 7.24–7.26 (m, 1 H), 3.83–4.12 (m, 4 H),
1.53–1.72 (m, 4 H), 1.28–1.38(m, 4 H), 0.88 (t, J = 7.56 Hz, 6 H).
31P NMR (121 MHz, CDCl3): d = 33.57.
HRMS: m/z [M + H]+ calcd for C20H15BrF3NO2P: 467.9976; found:
467.9982.
Synthesis 2008, No. 21, 3473–3477 © Thieme Stuttgart · New York

3476
D. Jiang et al.
PAPER
Diisopropyl 5-Bromo-2-(trifluoroacetamido)phenylphospho-
nate (3e)
Diisopropyl 4-Nitro-2-(trifluoroacetamido)phenylphosphonate
(3j)
Colorless oil; yield: 72%.
Red oil: yield: 87%.
1H NMR (300 MHz, CDCl3): d = 11.85 (s, 1 H), 8.42–8.45 (m, 1 H),
7.64–7.74 (m, 2 H), 4.68–4.71 (m, 2 H), 1.38 (d, J = 6.18 Hz, 6 H),
1.23 (d, J = 6.18 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 155.2 (q, J = 38.2 Hz), 138.6,
136.8, 135.3, 135.2, 122.6, 122.3, 118.1 (m), 72.9, 23.8.
31P NMR (121 MHz, CDCl3): d = 14.80.
HRMS: m/z [M + H]+ calcd for C14H19BrF3NO4P: 432.0187; found:
1H NMR (300 MHz, CDCl3): d = 7.39–7.57 (m, 3 H), 4.46–4.66 (m,
2 H), 1.34 (d, J = 6.18 Hz, 6 H), 1.20 (d, J = 6.18 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 151.7 (q, J = 37.3 Hz), 134.9,
134.6, 116.9 (m), 110.5, 110.4, 110.3, 110.2, 71.7, 24.0.
31P NMR (121 MHz, CDCl3): d = 16.38.
HRMS: m/z [M + H]+ calcd for C14H19F3N2O6P: 399.0933; found:
399.0937.
432.0186.
Acknowledgment
[5-Methyl-2-(trifluoroacetamido)phenyl]diphenylphosphine
Oxide (3f)
This work was supported by the National Natural Science Founda-
tion of China (Grant No. 20672065 and 20732004), Chinese 863
Project (Grant No. 2007AA02Z160), Programs for New Century
Excellent Talents in University (NCET-05-0062) and Changjiang
Scholars and Innovative Research Team in University (PCSIRT)
(No. IRT0404) in China and the Key Subject Foundation from
Beijing Department of Education (XK100030514).
Colorless oil; yield: 78%.
1H NMR (300 MHz, CDCl3): d = 8.41–8.44 (m, 1 H), 7.43–7.67 (m,
11 H), 6.91 (d, J = 6.78 Hz, 1 H), 2.24 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 155.2 (q, J = 37.2 Hz), 134.3,
133.1, 132.9, 132.8, 132.4, 132.2, 132.0, 131.6, 129.0, 122.3, 122.2,
118.3 (m), 21.1.
31P NMR (121 MHz, CDCl3): d = 33.90.
HRMS: m/z [M + H]+ calcd for C21H18F3NO2P: 404.1027; found:
References
404.1029.
(1) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029; and
references therein.
Dibutyl 5-Methyl-2-(trifluoroacetamido)phenylphosphonate
(3g)
Colorless oil; yield: 91%.
1H NMR (300 MHz, CDCl3): d = 11.77 (s, 1 H), 8.42 (t, J = 7.52 Hz,
1 H), 7.37–7.42 (m, 2 H), 3.97–4.11 (m, 4 H), 2.35 (s, 3 H), 1.54–
1.75 (m, 4 H), 1.29–1.41 (m, 4 H), 0.87 (t, J = 7.56 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 154.2 (q, J = 37.4 Hz), 135.1,
134.9, 132.8, 132.7, 121.2, 121.0, 116.6 (m), 66.7, 32.3, 20.8, 18.6,
13.4.
(2) (a) Dolman, N. P.; More, J. C. A.; Alt, A.; Knauss, J. L.;
Troop, H. M.; Bleakman, D.; Collingridge, G. L.; Jane, D. E.
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Janda, K. D. Bioorg. Med. Chem. Lett. 2007, 17, 4280.
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X.-K.; Han, Y.-H.; Stallcup, W. B.; Fukushi, J.-I.; Mustelin,
T.; Tautz, L.; Su, Y.; Harris, D. L.; Waleh, N.; Hobbs, P. D.;
Jong, L.; Chao, W.-R.; Schiff, L. J.; Sani, B. P. J. Med.
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31P NMR (121 MHz, CDCl3) d = 19.52.
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HRMS: m/z [M + H]+ calcd for C17H26F3NO4P: 396.1552; found:
1961, 26, 3270.
(4) See selected examples: (a) Ngo, H. L.; Lin, W. J. Am. Chem.
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Bunel, E. E.; Faul, M. M.; Larsen, R. D.; Martinelli, M. J.
J. Org. Chem. 2007, 72, 5104.
396.1558.
Diisopropyl 5-Methyl-2-(trifluoroacetamido)phenylphospho-
nate (3h)
Colorless oil; yield: 92%.
(5) (a) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem. Eur.
J. 2006, 12, 3636. (b) Huang, C.; Tang, X.; Fu, H.; Jiang, Y.;
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1H NMR (300 MHz, CDCl3): d = 11.80 (s, 1 H), 8.39 (t, J = 7.56 Hz,
1 H), 7.34–7.43 (m, 2 H), 4.62–4.67 (m, 2 H), 2.29 (s, 3 H), 1.37 (d,
J = 6.18 Hz, 6 H), 1.20 (d, J = 6.18 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 155.1 (q, J = 37.2 Hz), 134.6,
133.0, 132.9, 121.2, 120.9, 118.2 (m), 72.2, 23.9, 23.6.
31P NMR (121 MHz, CDCl3): d = 17.51.
HRMS: m/z [M + H]+ calcd for C15H22F3NO4P: 368.1239; found:
368.1246.
Dibutyl 4-Nitro-2-(trifluoroacetamido)phenylphosphonate (3i)
Yellow oil; yield: 56%.
1H NMR (300 MHz, CDCl3): d = 7.38–7.54 (m, 3 H), 3.87–4.05 (m,
4 H), 1.58–1.63 (m, 4 H), 1.31–1.37 (m, 4 H), 0.81–0.87 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 152.1 (q, J = 37.3 Hz), 134.7,
134.6, 118.2 (m), 115.1, 110.5, 110.3, 110.2, 66.4, 32.3, 18.7, 13.5.
31P NMR (121 MHz, CDCl3): d = 18.65.
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HRMS: m/z [M + H]+ calcd for C16H23F3N2O6P: 427.1246; found:
427.1244.
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Copper-Catalyzed Coupling of 2-Haloacetanilides with Phosphorus Compounds
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Synthesis 2008, No. 21, 3473–3477 © Thieme Stuttgart · New York