Efficient palladium-catalyzed synthesis of aminopyridyl phosphonates from bromopyridines and diethyl phosphite

Article abstract of DOI:10.1055/s-2008-1072570

A general method for coupling aminopyridyl bromides with diethyl phosphite is reported. This efficient route is realized through the use of a palladium catalyst and triethylamine as base. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072570

PAPER
1575
Efficient Palladium-Catalyzed Synthesis of Aminopyridyl Phosphonates from
Bromopyridines and Diethyl Phosphite
P
alladium-Catalyz
l
e
d
Syn
l
o
a
f
A
minopyridyl
P
B
hosphonates essmertnykh, Christiane Morkos Douaihy, Sankar Muniappan, Roger Guilard*
Institut de Chimie Moléculaire, Université de Bourgogne (ICMUB) - UMR 5260 CNRS, 9, av. Alain Savary, 21078 Dijon, France
Fax +33(3)80396138; E-mail: Roger.Guilard@u-bourgogne.fr
Received 15 January 2008
Br
P(O)(OEt)2
H2N
H2N
Abstract: A general method for coupling aminopyridyl bromides
with diethyl phosphite is reported. This efficient route is realized
through the use of a palladium catalyst and triethylamine as base.
Pd(OAc)2
HP(O)(OEt)2
+
ligand,
base
N
N
Key words: palladium, catalysis, phosphonates, cross-coupling,
pyridyl halides
Equation 1
precatalyst [Pd(OAc)2] and 30 mol% of triphenylphos-
The formation of carbon–heteroatom bonds (C–N, C–O, phine allowed the transformation of the bromide 1 into di-
C–S and C–P) by transition-metal-catalyzed cross- ethyl 5-methyl-2-aminopyridylphosphonate (2).
coupling methodology has been the subject of intensive
The reaction was performed using diethyl phosphite (1.2
investigations in recent years and a great variety of new
equiv) and triethylamine (1.5 equiv) as a base with 1 (1
equiv) in refluxing solvent. The nature of the solvent is a
efficient synthetic approaches leading to key compounds
have been developed.1 Palladium-catalyzed reaction of
key parameter of the reaction course. Toluene was found
aryl halides with dialkyl phosphite disclosed by Hirao,2 is
to be ineffective as solvent and complete transformation
the most attractive route to aryl dialkylphosphonates.3 Py-
could not be achieved in acetonitrile (entries 1 and 2). It
ridyl and bipyridyl phosphonates can also be obtained ac-
was surprising that ethanol, which is an inefficient solvent
cording to this procedure.2,4 However, the strong
in the cross-coupling reaction of 3-bromopyridine with di-
coordination properties of the pyridine moiety can inter-
ethyl phosphite,9 could be successfully used for the stud-
rupt the catalytic cycle and specific conditions have to be
ied reaction (entry 3) as well as THF (entry 4). Decreasing
determined for such reactions. For example, according to
the amount of palladium precatalyst to 5 mol% (entry 5)
Hirao’s conditions, a good yield was obtained in the syn-
or increasing the amount of ligand (entry 6) resulted in
thesis of pyridyl phosphonates starting from 3-bromopy-
lower conversion and yield. A slight increase in the reac-
ridine, but 2-iodo- and 2-bromopyridines were less
tion rate was observed when the precatalyst amount was
reactive and led to the corresponding derivatives in lower
increased to 12 mol% and the precatalyst/ligand ratio was
yields.5 A large excess of triphenylphosphine (a pyridyl
decreased to 2.5 (entry 7). In ligand screening studies (en-
tries 8–11) we found that 1,1¢-bis(diphenylphosphino)fer-
rocene (dppf) was more active than triphenylphosphine
bromide/ligand ratio of 1:10) was necessary to run a suc-
cessful synthesis of bipyridyl derivatives.6 Aminopy-
ridines are routinely used to prepare pharmaceuticals, hair
and led to the desired product in a good yield (entry 10).
dyes and precursors leading to new materials.7 A survey
Tri(cyclohexyl)phosphine, tri(2-tolyl)phosphine, 2,2¢-
of the literature reveals that photochemical reactions are
bis(diphenylphosphino)-1,1¢-binaphthyl (BINAP) were
the only efficient way with which to prepare dialkyl ami-
either less efficient or totally inefficient. Triethylamine
nopyridylphosphonates.5 Many attempts have clearly
was a suitable base in such coupling reactions. The use of
shown that, among the pyridine derivatives, aminopy-
inorganic bases such as Cs2CO3, K2CO3 and NaOH led to
ridines are one of the most difficult coupling partners due
the reduced product 3 in up to 90% conversion (entries
12–14). No reaction was observed with KH2PO4 (entry
to enhanced palladium complexation by the aminopyri-
dine moiety.8 In this paper, we wish to report a general
15).
method for palladium-catalyzed synthesis of aminopy-
On the basis of these preliminary outcomes, successful re-
ridyl phosphonates from aminopyridyl bromides and di-
actions were generally conducted in ethanol at reflux un-
ethyl phosphite (Equation 1).
der nitrogen atmosphere with diethyl phosphite (1.2
5-Methyl-2-amino-3-bromopyridine was selected as a
equiv) and palladium precursor (12 mol%) in combination
model substrate for palladium-catalyzed coupling reac-
with triphenylphosphine [ligand–Pd(OAc)2, 2.5] in the
tions (Table 1). Initial attempts to determine the optimal
presence of triethylamine (1.5 equiv).
reaction conditions revealed that 10 mol% of palladium
Under these general reaction conditions, diethyl phosphite
could be effectively coupled with a variety of bromide de-
SYNTHESIS 2008, No. 10, pp 1575–1579
Advanced online publication: 27.03.2008
DOI: 10.1055/s-2008-1072570; Art ID: P00808SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
8
rivatives. As summarized in Tables 2, 2-amino-5-bromo-
pyridine (entry 1), 2-amino-5-bromo-4-methylpyridine
(entry 2), 2-amino-5-bromo-3-methylpyridine (entry 3)

1576
A. Bessmertnykh et al.
PAPER
Table 1 Cross-Coupling of 5-Methyl-2-amino-3-bromopyridine (1) with Diethyl Phosphitea
Pd(OAc)2,
ligand,
base
Me
Me
Me
Br
P(O)(OEt)2
NH2
+
HP(O)(OEt)2
+
solvent, reflux
N
N
NH2
N
NH2
1
2
3
Entry
Ligand
{[Pd]/[ligand] (mol%)}
Base
Et3N
Et3N
Et3N
Solvent
Toluene
MeCN
EtOH
Time (h)
Conversion (%)b Yield (%)c
1
2
3
PPh3
(10:30)
24
48
0
0
0
PPh3
(10:30)
24
72
30
80
80
PPh3
(10:30)
24
30
48
50
70
100d
100
100
45
4
5
6
7
8
PPh3
(10:30)
Et3N
Et3N
Et3N
Et3N
Et3N
THF
24
48
50
100
PPh3
(5:15)
EtOH
EtOH
EtOH
EtOH
24
30
28
45
PPh3
(5:30)
24
30
13
29
29
PPh3
(12:30)
24
36
60
100
100
P(o-Tol)3
(10:30)
24
48
72
50
66
70
70
9
10
11
12
13
14
15
P(c-Hex)3
(10:30)
Et3N
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
24
48
13
22
13
22
dppf
(10:15)
Et3N
18
36
70
100
100e
BINAP
(10:15)
Et3N
24
48
12
24
24
10
PPh3
(10:30)
Cs2CO3
K2CO3
NaOH
KH2PO4
24
100
PPh3
(10:30)
24
100
30
PPh3
(10:30)
24
48
26
100
10
0
PPh3
(10:30)
24
48
0
0
a Reaction conditions: bromide 1 (1 mmol), diethyl phosphite (1.2 equiv), base (1.5 equiv), Pd(OAc)2 (5–12 mol%), ligand (15–30 mol%) in
solvent (4 mL) at reflux under N2.
b 1H NMR ratio (2+3)/(1+2+3).
c 1H NMR ratio 2/(1+2+3).
d Isolated yield was 82% (colorless solid).
e Isolated yield was 86% (brown solid, purity >97%).
and 5-amino-2-bromopyridine (entry 4) all give the de- (15 mol%); entry 4]. However, when 4-amino-3-bro-
sired phosphonates in good yields. It is noteworthy that mopyridine (entry 5) was reacted with diethyl phosphite,
full conversion of 5-amino-2-bromopyridine and im- the reaction was very slow and the desired product was
proved reaction yield were observed even with a de- isolated in low yield (31%). All attempts to improve con-
creased amount of catalyst [Pd(OAc)2 (5 mol%) and PPh3 ditions for this coupling reaction, based on the data ob-
Synthesis 2008, No. 10, 1575–1579 © Thieme Stuttgart · New York

PAPER
Palladium-Catalyzed Synthesis of Aminopyridyl Phosphonates
1577
Table 3 Cross-Coupling of 4-Amino-3-bromopyridine with Diethyl
tained in the prototypical reaction, were unsuccessful
(Table 3). The use of excess triphenylphosphine or diethyl
phosphite (entries 1, 2 and 3), other ligands (entries 4 and
5) or the use of THF as solvent (entry 6), did not afford
higher yield. It seems that the reaction depends on the
steric bulk of the pyridyl bromide. Indeed, o-bromo or o-
amino-substituted pyridines were more reactive due to the
decrease of the palladium complexation by the pyridine
fragment. The reduction of pyridyl bromides and the for-
mation of palladium–pyridine complexes were observed
as side reactions under these conditions. When 3,5-dibro-
mopyridine was used as a coupling partner (Table 2, entry
6), the triphenylphosphine-based system catalyzed double
cross-coupling reactions with diethyl phosphite, affording
the corresponding diphosphonates (60%) in a one-pot pro-
cedure.
Phosphitea
NH2
NH2
P(O)(OEt)2
Br
HP(O)(OEt)2
Pd(OAc)2,
ligand,
base
N
N
4
5
Entry Ligand
HP(O)(OEt)2 Solvent
Time Conversion
{[Pd]/[ligand] (equiv)
(mol%)}
(d)
(%)b
20
0
1
2
3
4
5
6
PPh3
(10:60)
1.2
1.2
2.4
1.2
1.2
1.2
EtOH
EtOH
EtOH
EtOH
EtOH
THF
5
PPh3
(10:400)
3
PPh3
(10:30)
5
50
0
In summary, we have determined the critical conditions
necessary for a general procedure for palladium-catalyzed
synthesis of aminopyridyl phosphonates from amino-
pyridyl bromides and diethyl phosphite.
Dppf
(10:15)
5
P(o-Tol)3
(10:30)
3
0
Table 2 Scope and Limitations of the Reaction Protocola
PPh3
5
40
Entry Substrate
Product
Yield (%)
(5:30)
O
a Reaction conditions: pyridyl bromide (1 mmol), diethyl phosphite,
Et3N (1.5 equiv), Pd(OAc)2 and ligand in solvent (4 mL) at reflux for
3 d under N2.
Br
P(OEt)2
1
56
H2N
N
b 1H NMR ratio 5/(4+5).
H2N
N
Me
Me
O
Br
Br
P(OEt)2
2
3
60
70
All chemicals were of commercial quality (Aldrich, Acros) used
from freshly opened containers. Ethanol was dried over magne-
sium. Preparative column chromatography was performed with
SDS silica gel 60 A C.C (Chromagel, particle size 70–200 mm). An-
alytical TLC was carried out with silica gel 60 F254 plates, Merck.
Melting points were measured on a Buchi B-545 apparatus and are
uncorrected. Elemental analyses were obtained from EA1108
CHNS Fisons Instrument analyser. NMR spectra were taken with
Bruker Avance 300 and 600 instruments with the chemical shifts
reported as d in ppm and scalar couplings expressed in Hz. Mass
spectra were recorded on Thermo DSQ II apparatus (EI, 70 eV).
H2N
Me
N
H2N
Me
N
N
O
P(OEt)2
H2N
H2N
N
H2N
H2N
73
4
5
6
80b
N
O
P(OEt)2
O
N
Br
Diethyl Aminopyridylphosphonates; General Procedure
A 25 mL round-bottom flask equipped with a reflux condenser and
a magnetic stirrer bar was charged with pyridyl bromide (1 mmol),
the indicated amount of Pd(OAc)2 and the ligand (Table 1 and
Table 2). The reaction vessel was evacuated and purged with N2
three times. Subsequently, solvent (4 mL), diethyl phosphite (154
mL, 1.2 mmol) and Et3N (210 mL, 1.5 mmol) were added via sy-
ringe. The reaction mixture was stirred at reflux until conversion of
the bromide was complete (1H NMR). After cooling, the reaction
mixture was evaporated under reduced pressure and the residue was
taken up in CH2Cl2 and the product was separated by column chro-
matography on silica gel.
NH2
NH2
N
Br
P(OEt)2
31
N
O
O
Br
Br
60c
(EtO)2P
P(OEt)2
H2N
N
H2N
N
a Reaction conditions: pyridyl bromide (1–2 mmol), diethyl phosphite
(1.2 equiv), Et3N (1.5 equiv), Pd(OAc)2 (12 mol%), PPh3 (30 mol%)
in EtOH (8 mL) at reflux for 48 h under N2.
b Pd(OAc)2 (5 mol%) and PPh3 (15 mol%) were employed.
c Reaction conditions: pyridyl bromide (4 mmol), diethyl phosphite
(2.4 equiv), Et3N (3.0 equiv), Pd(OAc)2 (12 mol%), PPh3 (30 mol%)
in EtOH (16 mL) at reflux for 28 h under N2.
Diethyl 2-Amino-5-methylpyridin-3-ylphosphonate (2)
Prepared from 5-methyl-2-amino-3-bromopyridine (374 mg, 2
mmol) following the general procedure and purified by column
chromatography (CH2Cl2–MeOH, 4%).
Colorless solid; mp 80–81 °C.
Synthesis 2008, No. 10, 1575–1579 © Thieme Stuttgart · New York

1578
A. Bessmertnykh et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 1.26 (t, J = 6.0 Hz, 6 H, CH3), 2.19
(s, 3 H, CH3), 4.05 (m, 4 H, CH2), 5.68 (br s, 2 H, NH2), 7.50 (dd,
J = 15.2, 1.9 Hz, 1 H, H-4), 7.96 (d, J = 1.9 Hz, 1 H, H-6).
13C NMR (75 MHz, CDCl3): d = 16.2 (d, J = 6.7 Hz), 17.2, 62.3 (d,
J = 4.5 Hz), 103.5 (d, J = 185.3 Hz), 121.8 (d, J = 10.5 Hz), 142.9
(d, J = 6.8 Hz), 153.2, 158.3 (d, J = 10.5 Hz).
Colorless solid; mp 82–83 °C.
1H NMR (300 MHz, CDCl3): d = 1.23 (t, J = 6.0 Hz, 6 H, CH3), 2.08
(s, 3 H, CH3), 4.04 (m, 4 H, CH2), 4.92 (br s, 2 H, NH2), 7.54 (ddd,
J = 12.1, 1.6, 0.9 Hz, 1 H, H-4), 8.25 (dd, J = 6.6, 1.6 Hz, 1 H, H-2).
13C NMR (75 MHz, CDCl3): d = 16.3 (d, J = 6.5 Hz), 16.9, 61.9 (d,
J = 5.3 Hz), 112.6 (d, J = 198.6 Hz), 116.0 (d, J = 12.3 Hz), 140.2
(d, J = 9.8 Hz), 150.2 (d, J = 13.8 Hz), 159.9.
31P NMR (121 MHz, CDCl3): d = 19.16.
MS (EI, 70 eV): m/z (%) = 108.0 (60), 135.0 (15), 170.0 (32), 171.0
31P NMR (121 MHz, CDCl3): d = 19.12.
(46), 172.0 (58), 187.9 (100), 216.0 (68), 244.0 (100) [M]+.
MS (EI, 70 eV): m/z (%) = 108.0 (55), 135.0 (18), 170.0 (48), 171.0
(46), 172.0 (46), 188.0 (64), 216.0 (74), 244.0 (100) [M]+.
Diethyl 6-Aminopyridin-3-ylphosphonate (Table 2, Entry 1)
Prepared from 2-amino-5-bromopyridine (346 mg, 2 mmol) follow-
ing the general procedure and purified by column chromatography
(CH2Cl2–MeOH, 4%→5%).
Anal. Calcd for C10H17N2O3P: C, 49.18; H, 7.02; N, 11.47. Found:
C, 49.66; H, 7.20; N, 11.38.
Diethyl 5-Aminopyridin-2-ylphosphonate (Table 2, Entry 4)
Prepared from 5-amino-2-bromopyridine (173 mg, 1 mmol) follow-
ing the general procedure and purified by column chromatography
(CH2Cl2–MeOH, 5%).
Yield: 212 mg (46%); colorless solid; mp 113–114 °C.
A scale-up experiment was carried out using 2-amino-5-bromo-
pyridine (8 g, 46.2 mmol). After cooling, the reaction mixture was
evaporated under reduced pressure. The residue was taken up in tol-
uene (150 mL), triethylammonium bromide was filtered off and the
filtrate was evaporated under vacuum. The product was separated
by column chromatography on silica gel (CH2Cl2–MeOH,
4%→5%).
Colorless solid; mp 102–103 °C.
1H NMR (300 MHz, CDCl3): d = 1.32 (t, J = 7.0 Hz, 6 H, CH3), 4.10
(m, 4 H, CH2), 5.12 (br s, 2 H, NH2), 6.53 (dd, J = 8.5, 2.0 Hz, 1 H,
H-5), 7.76 (ddd, J = 11.8, 8.8, 2.2 Hz, 1 H, H-2), 8.44 (dd, J = 7.1,
2.0 Hz, 1 H, H-2).
13C NMR (75 MHz, CDCl3): d = 16.3 (d, J = 6.7 Hz), 62.0 (d,
J = 5.3 Hz), 107.9 (d, J = 12.9 Hz), 112.3 (d, J = 199.8 Hz), 140.8
(d, J = 10.0 Hz), 152.7 (d, J = 14.7 Hz), 160.9.
Yield: 5.93 g (56%).
1H NMR (300 MHz, CDCl3): d = 1.25 (t, J = 6.5 Hz, 6 H, CH3), 4.05
(m, 4 H, CH2), 4.50 (br s, 2 H, NH2), 6.90 (ddd, J = 7.9, 5.2, 2.0 Hz,
1 H, H-4), 7.65 (dd, J = 7.9, 6.2 Hz, 1 H, H-3), 8.15 (d, J = 2.7 Hz,
1 H, H-6).
31P NMR (121 MHz, CDCl3): d = 18.87.
13C NMR (75 MHz, CDCl3): d = 16.3 (d, J = 6.4 Hz), 62.5 (d,
J = 5.7 Hz), 119.0 (d, J = 13.7 Hz), 129.4 (d, J = 28.1 Hz), 138.4 (d,
J = 236.0 Hz), 139.4, 145.3 (d, J = 3.1 Hz).
31P NMR (121 MHz, CDCl3): d = 18.83.
MS (EI, 70 eV): m/z (%) = 93.7 (74), 120.7 (20), 155.8 (28), 156.8
(59), 157.8 (53), 173.7 (100), 201.6 (60), 229.7 (38) [M]+.
Anal. Calcd for C9H15N2O3P: C, 46.96; H, 6.57; N, 12.17. Found:
C, 47.07; H, 6.91; N, 11.89.
MS (EI, 70 eV): m/z (%) = 94.0 (75), 121.0 (48), 139.0 (24), 140.0
(26), 156.0 (48), 157.0 (42), 158.0 (42), 174.0 (56), 201.1 (45),
202.1 (52), 229.1 (30), 230.1 (100) [M]+.
Diethyl 4-Aminopyridin-3-ylphosphonate (Table 2, Entry 5)
Prepared from 4-amino-3-bromopyridine (173 mg, 1 mmol) follow-
ing the general procedure and purified by column chromatography
(CH2Cl2–MeOH, 5%).
Anal. Calcd for C9H15N2O3P: C, 46.96; H, 6.57; N, 12.17. Found:
C, 47.24; H, 6.60; N, 11.86.
Purity >97% (traces of PPh3O); yellow oil.
1H NMR (300 MHz, CDCl3): d = 1.13 (t, J = 7.2 Hz, 6 H, CH3), 3.95
(m, 4 H, CH2), 5.81 (br s, 2 H, NH2), 6.33 (d, J = 6.0 Hz, 1 H, H-5),
7.98 (dd, J = 6.0, 1.4 Hz, 1 H, H-2), 8.21 (d, J = 8.2 Hz, 1 H, H-6).
13C NMR (75 MHz, CDCl3): d = 16.2 (d, J = 6.7 Hz), 62.2 (d,
J = 5.3 Hz), 104.6 (d, J = 183.8 Hz), 110.3 (d, J = 9 Hz), 152.1,
153.7 (d, J = 9.7 Hz), 156.6 (d, J = 7.5 Hz).
Diethyl 6-Amino-4-methylpyridin-3-ylphosphonate (Table 2,
Entry 2)
Prepared from 2-amino-5-bromo-4-methylpyridine (374 mg, 2
mmol) following the general procedure and purified by column
chromatography (CH2Cl2–MeOH, 4%→5%).
Colorless solid; mp 126–127 °C.
31P NMR (121 MHz, CDCl3): d = 18.88.
1H NMR (300 MHz, CDCl3): d = 1.24 (t, J = 6.9 Hz, 6 H, CH3), 2.33
(s, 3 H, CH3), 4.05 (m, 4 H, CH2), 5.06 (br s, 2 H, NH2), 6.28 (d,
J = 3.9 Hz, 1 H, H-5), 8.37 (d, J = 7.8 Hz, 1 H, H-2).
13C NMR (75 MHz, CDCl3): d = 16.2 (d, J = 6.7 Hz), 20.8 (d,
J = 3.0 Hz), 61.7 (d, J = 5.3 Hz), 109.6 (d, J = 12.8 Hz), 130.1 (d,
J = 186.6 Hz), 151.7 (d, J = 10.5 Hz), 154.2 (d, J = 15.3 Hz), 161.6
(d, J = 1.5 Hz).
MS (EI, 70 eV): m/z (%) = 94.0 (37), 120.0 (36), 139.9 (22), 155.9
(41), 157.0 (36), 158.0 (36), 173.9 (46), 202.0 (48), 230.0 (100)
[M]+.
Tetraethyl 2-Aminopyridin-3,5-diyldiphosphonate (Table 2,
Entry 6)
Prepared from 2-amino-3,5-dibromopyridine (1.008 g, 4 mmol) fol-
lowing the general procedure. The reaction mixture was purified by
chromatography (CH2Cl2–MeOH, 4%).
31P NMR (121 MHz, CDCl3): d = 19.63.
MS (EI, 70 eV): m/z (%) = 108.0 (60), 135.0 (15), 170.0 (32), 171.0
(46), 172.0 (58), 187.9 (100), 216.0 (68), 244.0 (100) [M]+.
Colorless solid; mp 63–64 °C.
Anal. Calcd for C10H17N2O3P·0.5H2O: C, 45.19; H, 6.74; N, 11.71.
Found: C, 44.97; H, 6.68; N, 11.13.
A scale-up experiment was carried out using 2-amino-3,5-dibro-
mopyridine (10 g, 39.7 mmol). After cooling, the reaction mixture
was evaporated under reduced pressure. The residue was taken up
in toluene (150 mL), triethylammonium bromide was filtered off
and the filtrate was evaporated under vacuum. The product was pu-
rified by column chromatography on silica gel (CH2Cl2–MeOH,
4%). Yield: 11.26 g (79%).
Diethyl 6-Amino-5-methylpyridin-3-ylphosphonate (Table 2,
Entry 3)
Prepared from 2-amino-5-bromo-3-methylpyridine (374 mg, 2
mmol) following the general procedure and purified by column
chromatography (CH2Cl2–MeOH, 4%→5%).
Synthesis 2008, No. 10, 1575–1579 © Thieme Stuttgart · New York

PAPER
Palladium-Catalyzed Synthesis of Aminopyridyl Phosphonates
1579
1H NMR (300 MHz, CDCl3): d = 1.26 (t, J = 6.9 Hz, 6 H, CH3), 1.27
(t, J = 6.9 Hz, 6 H, CH3), 4.03 (m, 8 H, CH2), 6.75 (br s, 2 H, NH2),
8.00 (ddd, J = 15.2, 12.6, 2.2 Hz, 1 H, H-4), 8.43 (ddd, J = 6.2, 2.3,
2.3 Hz, 1 H, H-2).
13C NMR (75 MHz, CDCl3): d = 16.2 (d, J = 6.7 Hz), 62.4 (d,
J = 5.3 Hz), 103.9 (d, J = 185.3 Hz), 112.8 (d, J = 10.5 Hz), 142.6
(d, J = 4.5 Hz), 153.0, 160.21 (d, J = 5.6 Hz).
(3) For Ni- or Cu-mediated coupling of aryl halides with trialkyl
phosphites, see: (a) Tavs, P.; Korte, F. Tetrahedron 1967,
23, 4677. (b) Tavs, P. Chem. Ber. 1970, 103, 2428.
(c) Osuka, A.; Ohmasa, N.; Yoshida, Y.; Suzuki, H.
Synthesis 1983, 69. (d) Yuan, C.; Feng, H. Synthesis 1990,
140. (e) Czech, B. P.; Desai, D. H.; Koszuk, J.; Czech, A.;
Babb, D. A.; Robison, T. W.; Bartsch, R. A. J. Heterocycl.
Chem. 1992, 29, 867. (f) For Cu-promoted coupling of aryl
halides with dialkyl phosphites, see: Ogawa, T.; Usuki, N.;
Ono, N. J. Chem. Soc., Perkin Trans. 1 1998, 2953. (g) For
Cu-catalyzed coupling of aryl iodides with dialkyl
phosphites, see: Gelman, D.; Jiang, L.; Buchwald, S. L. Org.
Lett. 2003, 5, 2315. (h) For Cu-catalyzed reactions of
diazonium salt with PCl3, see: Freedman, L. D.; Doak, G. O.
J. Am. Chem. Soc. 1955, 77, 173. (i) For Friedel–Crafts
reaction of arenes with phosphorous derivatives, see:
Kosolapoff, G. M. J. Am. Chem. Soc. 1952, 74, 4119.
(j) For nucleophilic substitution reaction of activated aryl
halides with sodium dialkylphosphites, see: Boumekouez,
A.; About-Jaudet, E.; Savignac, N. C. P. J. Organomet.
Chem. 1992, 440, 297. (k) For SRN1 substitution reaction of
aryl halides with sodium dialkylphosphites, see:
Beugelmans, R.; Chbani, M. Bull. Soc. Chim. Fr. 1995, 132,
290.
31P NMR (121 MHz, CDCl3): d = 17.19 (d, J = 3.6 Hz), 17.40 (d,
J = 3.6 Hz).
MS (EI, 70 eV): m/z (%) = 155.9 (17), 173.9 (23), 202.0 (40), 218.9
(32), 229.0 (46), 230.0 (64), 257.0 (56), 258.1 (40), 338.0 (32),
366.0 (100) [M]+.
Anal. Calcd for C13H24N2O6P2·0.5H2O: C, 41.61; H, 6.71; N, 7.46.
Found: C, 41.99; H, 6.75; N, 7.46.
Acknowledgment
This work was supported by the CNRS and Conseil Régional de
Bourgogne. S.M. gratefully acknowledges the ‘Région de Bour-
gogne’ for a fellowship.
References
(4) (a) Johansson, T.; Stawinski, J. Chem. Commun. 2001,
2564. (b) Ayyappan, P.; Evans, O. R.; Foxman, B. M.;
Wheeler, K. A.; Warren, T. H.; Lin, W. Inorg. Chem. 2001,
40, 5954. (c) Ayyappan, P.; Evans, O. R.; Cui, Y.; Wheeler,
K. A.; Lin, W. Inorg. Chem. 2002, 41, 4978. (d) Ziessel, R.
F.; Charbonniere, L. J.; Mameri, S.; Camerel, F. J. Org.
Chem. 2005, 14, 9835.
(1) For reviews, see: (a) Muci, A. R.; Buchwald, S. L. Top.
Curr. Chem. 2002, 219, 131. (b) Hartwig, J. F. In Handbook
of Organopalladium Chemistry for Organic Synthesis, Vol.
1; Negishi, E.-I., Ed.; Wiley-Interscience: New York, 2002.
(c) Beletskaya, I. P. Pure Appl. Chem. 1997, 69, 471.
(2) (a) Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T.
Synthesis 1981, 56. (b) Hirao, T.; Masunaga, T.; Yamada,
N.; Ohshiro, Y.; Agawa, T. Bull. Chem. Soc. Jpn. 1982, 55,
909. (c) Petrakis, K. S.; Nagabhushan, T. L. J. Am. Chem.
Soc. 1987, 109, 2831. (d) Kabachnik, M. M.; Solntseva, M.
D.; Izmer, V. V.; Novikova, Z. S.; Beletskaya, I. P. Russ. J.
Org. Chem. 1998, 34, 93. (e) Defacqz, N.; de Bueger, B.;
Touillaux, R.; Cordi, A.; Marchand-Brynaert, J. Synthesis
1999, 1368. (f) Ngo, H. L.; Lin, W. J. Am. Chem. Soc. 2002,
124, 14298.
(5) Bulot, J. J.; Aboujaoude, E. E.; Collignon, N.; Savignac, P.
Phosphorus, Sulfur Relat. Elem. 1984, 21, 197.
(6) Penicaud, V.; Odobel, F.; Bujoli, B. Tetrahedron Lett. 1998,
39, 3689.
(7) (a) Yates, F. S. Pyridines and their Benzo Derivatives: (vi)
Applications, In Comprehensive Heterocyclic Chemistry.
The Structure, Reactions, Synthesis and Uses of
Heterocyclic Compounds, Vol. 2; Katritzky, A. R.; Rees, C.
W., Eds.; Pergamon Press: Oxford, 1984. (b) Pyridine and
its Derivatives, Part 5; Newkome, G. R., Ed.; Wiley-
Interscience: New York, 1984. (c) The Merck Index: An
Encyclopedia of Chemicals, Drugs and Biologicals; Merck
Research Laboratories Division of Merck & CO., INC.:
Whitehouse Station NJ, 2001.
(8) Pierrat, P.; Gros, P. C.; Fort, Y. J. Comb. Chem. 2005, 7,
879.
(9) Gooßen, L. J.; Dezfuli, M. K. Synlett 2005, 445.
Synthesis 2008, No. 10, 1575–1579 © Thieme Stuttgart · New York