Revisiting the Hirao cross-coupling: improved synthesis of aryl and heteroaryl phosphonates

Article abstract of DOI:10.1016/j.jorganchem.2008.07.020

The palladium-catalyzed cross-coupling of dialkylphosphite with aromatic electrophiles (Hirao coupling) was re-investigated. Some limitations in terms of palladium loadings and substrate reactivity are alleviated with the use of Pd(OAc)₂ comple

Full text of DOI:10.1016/j.jorganchem.2008.07.020

Journal of Organometallic Chemistry 693 (2008) 3171–3178
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Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Revisiting the Hirao cross-coupling: improved synthesis of aryl and heteroaryl
phosphonates
*
Yamina Belabassi, Saeed Alzghari, Jean-Luc Montchamp
Department of Chemistry, Box 298860, Texas Christian University, Fort Worth, TX 76129, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The palladium-catalyzed cross-coupling of dialkylphosphite with aromatic electrophiles (Hirao coupling)
was re-investigated. Some limitations in terms of palladium loadings and substrate reactivity are allevi-
ated with the use of Pd(OAc)2 complexed to 1,10-bis(diphenylphosphino)ferrocene (dppf) as a ligand. Var-
ious aryl and heteroaryl halides are employed to deliver both known and novel substituted
phosphonates. The first examples of aryl chloride couplings are also reported.
Received 13 July 2008
Accepted 14 July 2008
Available online 22 July 2008
Keywords:
Ó 2008 Elsevier B.V. All rights reserved.
Cross-coupling
Phosphorus
Palladium
Heterocycles
Aryl halides
1. Introduction
need for heterocyclic phosphonic acids for the development of me-
tal-organic frameworks (MOFs) [8], we decided to re-investigate
Hirao and co-workers reported in the early eighties the palla-
dium-catalyzed cross-coupling of dialkylphosphites with aromatic
halides (Eq. (1)) [1]. Since that time, the reaction has been widely
employed to prepare functionalized phosphonates [2]. While some
transition-metal (Ni, Cu) couplings forming phosphonates were
known much earlier [3], the Hirao reaction has established itself
as a fixture in phosphorus–carbon bond formation [4]. More recent
work by Buchwald [5] and Fu [6] has aimed at replacing palladium
with copper, and some useful results were obtained. One of the
reasons for avoiding palladium is its high cost, especially because
Hirao’s conditions employ 5 mol% Pd [1,2]. In an extensive survey
of the reaction, we could not find any example in which the cata-
lyst loading was lower than 3 mol%, and unfortunately, we were
not able to reproduce the yield reported for the latter conditions
[2d]. This prompted the present study
the Hirao coupling seeking conditions which would expand the
scope with respect to the aromatic electrophile substrates, as well
as reduce the quantity of palladium catalyst.
Our own cross-coupling investigations with hypophosphorous
derivatives [7d,e] had indicated that the ligand plays a crucial role,
and 1,3-bis(diphenylphosphino)propane (dppp) or 1,1’-bis(diphen-
ylphosphino)ferrocene (dppf) [9] were found to be best suited. Of
course, hypophosphorous compounds also feature the added com-
plication of the potential transfer hydrogenation pathways [7a,b].
While Hirao reported marginal problems with this side-reaction
[1], dialkylphosphites are much less prone to transfer hydrogena-
tion since they are weaker reducing agents than hypophosphorous
compounds. Initially, we wanted to prepare pyrazine-2-phos-
phonic acid for use in the preparation of metal organic frameworks
(MOFs), since pyrazine-2-COOH led to interesting results [10]. One
requirement for this objective is the preparation of multi-gram
quantities of the corresponding phosphonate diester precursor.
Additionally, our work with pyridyl phosphonic acids [8a,b] re-
vealed problems with 4-bromopyridine in spite of the literature
precedent [2d].
Reaction of 2-iodopyrazine, or of commercially available 2-chlo-
ropyrazine, failed under Hirao’s conditions. Fortunately, we soon
discovered that when dppf is used as a ligand, the reaction takes
place in good yield with 2-chloropyrazine, and with only 1 mol%
Pd. Herein we report our investigations using these improved reac-
tion conditions, which significantly expand upon the original Hirao
coupling and its subsequent implementations.
O
P
O
P
cat. Pd(PPh3)4
Et3N
RO
RO
RO
RO
ð1Þ
H
Ar
+ Et3N HX
ArX +
In connection with our ongoing work on the development of
phosphorus–carbon bond-forming reactions [7], as well as the
* Corresponding author. Tel.: +1 817 257 6501; fax: +1 817 257 5851.
E-mail address: j.montchamp@tcu.edu (J.-L. Montchamp).
0022-328X/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2008.07.020

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Y. Belabassi et al. / Journal of Organometallic Chemistry 693 (2008) 3171–3178
reaction. Several factors appeared important: the amount of palla-
2. Results and discussion
dium employed, as well as the partial triethylamine-promoted deal-
kylation of the diethyl phosphonate product and diethylphosphite
reagent (Eq. (2)), which reduced the yield when some product was
formed. While Hirao reported isolated examples on the use of diiso-
propyl phosphite in his seminal work, the importance of this was not
discussed [1]. Because dealkylation takes place via SN2, a secondary
ester would be better suited, and a more hindered base was also ex-
pected to reduce this side-reaction. We therefore investigated the
direct cross-coupling reaction of aryl and heteroaryl electrophiles
Hirao prepared aryl phosphonates from aryl bromides or iodides
using Pd(PPh3)4 as the catalyst and triethylamine as the base [1]. The
best results were obtained in the absence of a solvent. Subsequent
work generally employed similar conditions [2]. However, when
we tried applying these conditions with a reduced amount of palla-
dium, yields were significantly reduced. Using 5 mol% Pd is a major
drawback especially on large, multi-gram scales. Additionally, some
substrates gave low yields or no yield at all in the P–C bond-forming
Table 1
Scope of the cross-coupling with heterocyclic halides
Entry
1
Substrate
X
Solvent
CH3CN
Temperature
Reflux
Product
31P NMR (ppm)
9.9
Isolated yielda (%)
85
Br
O
P
i
i
-PrO
-PrO
X
N
i
N
O
P
-PrO
-PrO
X
2
Br
Br
CH3CN
DMF
Reflux
110 °C
14.6
13.6
61
48
N
i
N
O
P
3b
DMF
110 °C
63
i
-PrO
-PrO
X
NH.Cl
N
i
O
P
i
-PrO
-PrO
4
Br
Br
DMF
110 °C
7.6
30
67
i
N
N
X
X
N
X
Br
O
P
N
i
i
i
-PrO
5
6
CH3CN
Reflux
4.7
10.9
7.7
i-PrO
N
N
N
O
P
Cl
Br
DMF
CH3CN
110 °C
Reflux
62
83
N
N
N
-PrO
-PrO
X
X
i
N
O
P
N
-PrO
-PrO
7
Cl
CH3CN
Reflux
97
i
N
N
a
Isolated yield of pure compounds after chromatography on silica gel.
3 equiv of Et3N used instead of 1.3 equiv of i-Pr2NEt.
b
Table 2
Scope reaction on unprotected and Boc-protected anilines
Entry
1b
Substrate
X
X
I
Solvent
DMF
Temperature
Product
31P NMR (ppm)
20.2
Isolated yielda (%)
70
110 °C
i-PrO
P
i-PrO
H2N
H2N
O
P
i
-PrO
-PrO
X
2
3
I
I
CH3CN
CH3CN
Reflux
Reflux
18.5
19.2
72
70
i
NH2
NH2
NH2
O
P
i
-PrO
-PrO
X
X
NH2
i
O
P
i
-PrO
-PrO
I
Br
DMF
CH3CN
110 °C
Reflux
92
81
O
O
i
O
O
4
17.4
18.1
HN
HN
O
P
i-PrO
X
NH
O
NH
O
5
Br
CH3CN
Reflux
82
O
i-PrO
O
a
Isolated yield of pure compounds after silica gel chromatography.
Reaction conducted in a sealed tube.
b

Y. Belabassi et al. / Journal of Organometallic Chemistry 693 (2008) 3171–3178
3173
O
P
O
P
with N,N-diisopropylethylamine and diisopropyl phosphite (i-PrO)2
P(O)H [11] since this combination is expected to minimize
dealkylation (Eq. (2)). The test reaction was the synthesis of dialkyl
2-pyrazine phosphonate. Under Hirao’s conditions, no product
formed even with 2-iodopyrazine. After screening various cata-
lyst/ligand systems, Pd(OAc)2 (1 mol%) complexed to dppf gave
the most satisfactory result (67% yield) when reacted with 2-chloro-
pyrazine and diethylphosphite [(EtO)2P(O)H] in the presence of
triethylamine. However, some dealkylation (ca. 20%) was also
observed. The lower amount of catalyst was an encouraging element
from an economic point of view, but the reaction still required some
improvement. Although Et3N can be used successfully, i-Pr2NEt was
superior in order to suppress unwanted dealkylation.
RO
RO
O
P
O
P
H
Ar
R'3N
heat
RO
RO
RO
RO
O
O
and
and
H
Ar
R'3NR
R'3NR
ð2Þ
ð3Þ
1.0 equiv ArX
1.3 equiv -Pr2NEt
O
O
P
i
i
-PrO
i
-PrO
-PrO
P H
Ar
i
-PrO
i
1 mol% Pd(OAc)2/dppf
solvent, t οC, 24h
1.2 equiv
The solvent choice also impacted the reaction. Most of the reac-
tions proceeded well in acetonitrile but in some cases, the use of
N,N-dimethylformamide (DMF) provided better results. Once we
had determined the best reaction conditions (Eq. (3)) for the mod-
ified Hirao coupling, we investigated the scope of this process on a
wide range of aromatic and non-aromatic halides. The reactions
were carried out by adding the dialkylphosphite, aryl halide, base,
and then Pd(OAc)2 with dppf. The reaction mixture was then
heated at reflux in CH3CN, or at 110 °C in DMF, for 24 h under
nitrogen.
The conversion of nitrogen-containing heteroaromatic sub-
strates proceeded in moderate to excellent isolated yields (Table
1). Gooßen and Dezfuli also tried to improve the Pd-catalyzed
cross-coupling reaction of diethyl phosphite with various aryl bro-
mides by using 1.5 equiv. (c-Hex)2NMe as a base, 2 mol% of
Pd(OAc)2, and 6 mol% PPh3 in refluxing ethanol [12]. These condi-
tions were limited to some substrates and they were not able to
form the corresponding phosphonate from 3-bromopyridine [12].
On the other hand, Hirao obtained this compound in 77% isolated
O
Cl
Cl
CN
OCH3
O
P
O
P
O
P
O
i-PrO
i-PrO
i-PrO
i-PrO
i-PrO
i-PrO
H
CN
OCH3
31P-NMR: 14.7 ppm
44% isolated yield
in DMF, 110 o
C
31P-NMR: 14.2 ppm
57% isolated yield
Cl
CF3
1
2
O
P
i-PrO
i-PrO
31P-NMR: 16.5 ppm
22% isolated yield
3
CF3
Scheme 1. First cross-coupling with aryl chlorides.
Table 3
Scope of the reaction with activated and deactivated aryl halides
Entry
1
Substrate
X
Solvent
CH3CN
Temperature
Reflux
Product
31P NMR (ppm)
17.8
Isolated yielda (%)
99
O
Br
O
O
P
i
-PrO
-PrO
O
O
X
i
OCH3
OCH3
OCH3
NO2
OCH3
OCH3
OCH3
NO2
O
P
i
-PrO
-PrO
2
3
4
Br
Br
Br
CH3CN
DMF
Reflux
110 °C
110 °C
18.3
13.9
19.3
61
60
46
X
X
i
O
P
i
-PrO
-PrO
i
O
P
DMF
i-PrO
-PrO
X
i
N
N
5b
TfO
I
DMF
110 °C
17.8
17.6
86
93
O
P
i
-PrO
-PrO
X
X
i
O
P
i
-PrO
-PrO
6
CH3CN
Reflux
i
TfO
I
I
Br
Br
DMF
CH3CN
DMF
CH3CN
DMF
110 °C
Reflux
110 °C
Reflux
110 °C
47
27
51
27
76
O
P
i
-PrO
7
19.9
X
OH
OH
i
-PrO
a
Isolated yield of pure compounds after chromatography on silica gel.
Reaction performed in a sealed tube.
b

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Y. Belabassi et al. / Journal of Organometallic Chemistry 693 (2008) 3171–3178
OH
OH
OiPr
OiPr
O
O
Cl
Br
P
P
1.2 equiv (
i
-PrO)2P(O)H
1.3 equiv
i
-Pr2NEt
TMSBr, CH2Cl2
69%
N
2.8 g
N
N
17.5 mmol
N
0.9 mol% Pd(OAc)2/dppf
CH3CN, reflux, 19 h
N
O
N
O
4
76%
OiPr
OiPr
OH
OH
O
O
N
P
P
P
OH
1.2 equiv (i-PrO)2P(O)H
TMSBr, CH2Cl2
78%
1.3 equiv Et3N
5.8 g
+
35.9 mmol
N
N
N
N
N
N
0.5 mol% Pd(OAc)2/dppf
CH3CN, reflux
N
N
N
H
5 major
5 minor
72%
OiPr
OiPr
OH
O
N
O
N
Cl
Br
1.2 equiv (
1.3 equiv
i
-PrO)2P(O)H
P
P
P
OH
TMSBr, CH2Cl2
89%
i
-Pr2NEt
4.0 g
N
N
25.2 mmol
1 mol% Pd(OAc)2/dppf
DMF, 85 oC, 21 h
28%
6
OEt
OEt
O
O
O
P
OH
1.2 equiv (EtO)2P(O)H
1.3 equiv Et3N
TMSBr, CH2Cl2
100%
7.0 g
43.8 mmol
N
N
0.9 mol% Pd(OAc)2/dppf
CH3CN, reflux, 22 h
N
H
7
94%
Scheme 2. Preparation of some phosphonic acids.
yield using 5 mol% Pd(PPh3)4 [1a]. 4-Bromopyridine hydrochloride
was reported in the literature to give the desired product in 70%
isolated yield with 3 mol% Pd [2d], but under identical conditions,
we only obtained 30%. Following our new protocol with 1 mol%
Pd(OAc)2/dppf, in DMF at 110 °C, the product was obtained in good
isolated yield (entry 3). However, when reacting 1 equiv. of 2,6-
dibromopyridine, only 30% isolated yield of the monobromopyri-
dine phosphonate was obtained due to the expected competing
disubstitution (Table 1, entry 4). 2-Chloropyrimidine reacted as
well as the bromo analog affording the desired product in good
yield (Table 1, entry 5). In the literature, the thermal Arbuzov reac-
tion of 2-halopyrimidine was described [13], but when we per-
formed this reaction, violent decomposition took place.
Fortunately, 2-chloropyrazine (which was our initial entry into this
study) reacted very well under our conditions to provide diisopro-
pyl pyrazine phosphonate in 97% isolated yield.
Next, we turned our attention to aniline derivatives. Interest-
ingly, unprotected 2-iodoaniline (Table 2, entry 1) gave satisfactory
results in DMF at 110 °C. Similarly, the iodo aniline isomers pro-
vided satisfactory results (entries 2 and 3). Savignac and co-work-
ers reported on the failure of the Hirao coupling with unprotected
iodoanilines, and prepared the corresponding products using a
photostimulated nucleophilic substitution [14]. On the other hand,
Buchwald obtained the dibutylphosphonate analog in 86% yield,
using CuI (5 mol%) and N,N’-dimethylethylenediamine (20 mol%)
as the ligand with 2 equiv. of Cs2CO3 as the base [5].
Two Boc-protected anilines reacted uneventfully affording the
products in good yields (entries 4 and 5) and multi-gram scale syn-
theses were also performed easily. In addition, the 2-Boc-protected
aniline phosphonate (entry 4) was easily isolated by simply wash-
ing the solid obtained after work-up (see Scheme 1).
More examples of cross-coupling were investigated. A variety of
electron-poor and electron-rich substrates were also suitable and
the aryl phosphonate products were generally isolated in good to
excellent yields (Table 3). Reaction with iodobenzene and a re-
duced amount of palladium (0.1 mol% Pd) still gave an 82% isolated
yield after 48 h (compare with Table 3, entry 6). Gratified with the
overall results, we then investigated our conditions on a few aryl
chlorides. Apparently, there is no literature example on the suc-
cessful Pd-catalyzed cross-coupling reaction of a dialkyl phosphite
with any aryl chloride. We found that reacting diisopropyl phos-
phite in DMF, at 110 °C, with an activated (electron-poor) ArCl
led to the formation of the desired product in low to moderate
yields (Scheme 2) using our conditions (1 mol% Pd). Chlorobenzene
only gave a 22% NMR yield and the product was not isolated. These
results represent our first attempts using the standard conditions
reported herein, and although promising, further investigations
need to be conducted in order to further improve those yields.
Finally, the multi-gram scale implementation of the cross-cou-
pling was employed in the preparation of some heterocyclic phos-
phonic acids (Scheme 2) as potential metal organic framework
(MOFs) precursors. Deprotection of the phosphonate diesters using
McKenna’s protocol [15] gave excellent results. The phosphonate
diester precursors were prepared either using (i-PrO)2P(O)H/i-
Pr2NEt, or (EtO)2P(O)H/Et3N, with 0.5–1.0 mol% Pd. Since the com-
pounds are nitrogen-containing heterocycles, these intermediates
can be purified by acid–base extraction instead of chromatography.
The low yield observed in the case of the 2-pyrimidyl ester inter-
mediate is due to incomplete protonation of the pyrimidine phos-
phonate during work-up (compare with Table 1, entry 5), but no
attempt was made at optimizing this particular compound. Inter-
estingly, while the deprotected pyridine compounds such as 7 gen-
erally exist as the zwitterion, the 5-pyrimidine-derived phosphonic
acid 5 exists as a mixture of the neutral compound and the zwitter-
ion, and the pyrazine- or 2-pyrimidine phosphonic acids (4 and 6)
exist as the neutral compounds since the nitrogen atoms are very
weak bases [16].
3. Conclusion
We have developed an efficient, versatile and economically
attractive alternative to the original Hirao cross-coupling. A wide
variety of aryl and heteroaryl phosphonates, including many new
compounds, were synthesized using Pd(OAc)2/dppf (1 mol%) as
the catalyst. This cross-coupling is successful with various sub-
strates which gave low yields or entirely failed using Hirao’s and
other related conditions. The reaction is appropriate for multi-
gram scale implementation. In addition, the first examples of pal-
ladium-catalyzed P–C bond formation between an activated aryl
chloride and a phosphite are reported. While the yields are low

Y. Belabassi et al. / Journal of Organometallic Chemistry 693 (2008) 3171–3178
3175
to moderate, this indicates the possibility for further improvement.
Because dppf is widely available and relatively inexpensive, the
present cross-coupling should find some use in the preparation
of a variety of phosphonate diesters, and appears competitive to
the emerging copper-based systems.
138.4 (d, JPCCC = 12 Hz), 130.7 (d, JPCCCC = 3 Hz), 126.9 (d,
JPCC = 24 Hz), 72.5 (d, JPOC = 6 Hz, 2C), 24.3 (d, JPOCC = 4 Hz, 2C),
24.0 (d, JPOCC = 5 Hz, 2C); 31P NMR (CDCl3, 121.47 MHz) d 7.64
(s); HRMS (EI+) Calc. for C11H17BrNO3P, (M + H)+ 322.0208. Found:
322.0201.
4.6. Diisopropyl-2-pyrimidylphosphonate (Table 1, entry 5) [13]
4. Experimental
Yield: 62–67%. M.p. 51–57 °C. 1H NMR (CDCl3, 300 MHz) d 8.90
(d, J = 5.2 Hz, 2H), 7.45–7.40 (m, 1H), 5.02–4.88 (m, 2H), 1.44 (d,
J = 6.2 Hz, 6H), 1.35 (d, J = 6.2 Hz, 6H); 13C NMR (CDCl3,
75.45 MHz) d 164.1 (d, JPC = 273 Hz), 156.9 (d, JPCNC = 18 Hz, 2C),
122.5 (d, JPCNCC = 4 Hz), 72.4 (d, JPOC = 6 Hz, 2C), 24.0 (d,
JPOCC = 4 Hz, 2C), 23.6 (d, JPOCC = 4 Hz, 2C); 31P NMR (CDCl3,
121.47 MHz) d 4.7 (s).
4.1. Representative procedure for cross-coupling of aryl halide
substrates
To a solution of diisopropyl phosphite (4.8 mmol, 1.2 equiv.) in
CH3CN or DMF (both previously dried over 4 Å molecular sieves)
(see Tables 1–3) (15 mL), was added an aryl or heteroaryl halide
(4 mmol, 1.0 equiv.), N,N-diisopropylethylamine (5.2 mmol, 0.9 mL,
1.3 equiv.), Pd(OAc)2 (0.04 mmol, 1 mol%) and dppf (0.044 mmol,
1.1 mol%) at room temperature. The solution was heated for 24 h
at reflux in CH3CN, or at 110 °C in DMF, under nitrogen. After cool-
ing to room temperature, the crude mixture was concentrated in
vacuo and the residue was partitioned between de-ionized water
and EtOAc, followed by extraction of the aqueous phase with EtOAc
(3ꢀ). The organic fractions were combined and washed with brine
(1ꢀ). Drying and concentration furnished the crude compound,
which was purified by radial or column chromatography using
mixtures hexanes/EtOAc, unless otherwise specified.
4.7. Diisopropyl-5-pyrimidylphosphonate (Table 1, entry 6)
Yield: 83%. M.p. 30–32 °C. 1H NMR (CDCl3, 300 MHz) d 9.25
(s, 1H), 8.97 (d, J = 6.6 Hz, 2H), 4.76–4.66 (m, 2H), 1.32 (d, J =
6.0 Hz, 6H), 1.20 (d, J = 6.0 Hz, 6H); 13C NMR (CDCl3, 75.45 MHz)
d 160.8, 159.5 (d, JPCC = 5 Hz), 159.3 (d, JPCC = 5 Hz), 125.1 (d,
JPC = 192 Hz), 71.9 (d, JPOC = 6 Hz, 2C), 23.9 (d, JPOCC = 4 Hz, 2C),
23.8 (d, JPOCC = 5 Hz, 2C); 31P NMR (CDCl3, 121.47 MHz) d 10.9
(s); HRMS (EI+) Calc. for C10H17N2O3P, (M)+ 244.0977. Found:
244.0975.
4.2. Diisopropyl-2-pyridylphosphonate (Table 1, entry 1) [17]
4.8. Diisopropyl-2-pyrazylphosphonate (Table 1, entry 7)
Yield: 85%. 1H NMR (CDCl3, 300 MHz) d 8.81 (d, J = 4.5 Hz, 1H),
7.98 (dd, J = 7.2 Hz, J = 6.6 Hz 1H), 7.84–7.76 (m, 1H), 7.44–7.39
(m, 1H), 4.91–4.78 (m, 2H), 1.40 (d, J = 6.3 Hz, 6H), 1.28 (d,
Yield: 97%. 1H NMR (CDCl3, 300 MHz) d 9.02 (s, 1H), 8.64 (d,
J = 16.1 Hz, 2H), 4.86–4.75 (m, 2 H), 1.33 (d, J = 6.2 Hz, 6H), 1.23
(d, J = 6.2 Hz, 6H); 13C NMR (CDCl3, 75.45 MHz) d 148.9 (d,
JPC = 226 Hz), 147.7 (d, JPCC = 26 Hz), 146.7 (d, JPCCNC = 3 Hz), 145.2
(d, JPCNC = 18 Hz), 72.2 (d, JPOC = 6 Hz, 2C), 24.0 (d, JPOCC = 4 Hz,
2C), 23.8 (d, JPOCC = 4 Hz, 2 C); 31P NMR (CDCl3, 121.47 MHz) d
7.73 (s); HRMS (EI+) Calc. for C10H17N2O3P, (M)+ 244.0977. Found:
244.0977.
J = 6.3 Hz, 6H); 13C NMR (CDCl3, 75.45 MHz) d 152.7 (d, JPC
=
225 Hz), 150.1 (d, JPCNC = 23 Hz), 135.8 (d, JPCCC = 12 Hz), 127.5 (d,
JPCC = 27 Hz), 125.6, 71.1 (d, JPOC = 6 Hz, 2C), 23.7 (2C), 23.5 (2C);
31P NMR (CDCl3, 121.47 MHz) d 9.88 (s).
4.3. Diisopropyl-3-pyridylphosphonate (Table 1, Entry 2)
4.9. Diisopropyl-2-anilinylphosphonate (Table 2, entry 1)
Yield: 48–61%. 1H NMR (CDCl3, 300 MHz) d 9.20–8.86 (m, 1H),
8.78–8.70 (m, 1H), 8.18–8.02 (m, 1H), 7.42–7.36 (m, 1H), 4.81–
4.68 (m, 2H), 1.40 (d, J = 6.3 Hz, 6H), 1.26 (d, J = 6.3 Hz, 6H); 13C
NMR (CDCl3, 75.45 MHz) d 152.8, 152.3 (d, JPCC = 13 Hz), 139.4 (d,
JPCC = 8 Hz), 126.6 (d, JPC = 190 Hz), 123.4 (d, JPCCC = 12 Hz), 71.4
(d, JPOC = 6 Hz, 2C), 24.1 (d, JPOCC = 4 Hz, 2C), 23.9 (d, JPOCC = 5 Hz,
2C); 31P NMR (CDCl3, 121.47 MHz) d 14.4 (s); HRMS (EI+) calcd
for C11H18NO3P, (M)+ 243.1024, found 243.1022.
Yield: 70%. M.p. 46–47 °C. 1H NMR (CDCl3, 300 MHz) d 7.47
(ddd, J = 7.8 Hz, J = 1.7 Hz, 1H), 7.28–7.23 (m, 1H), 6.71–6.60 (m,
2H), 5.19 (s, 2H, NH2), 4.70–4.58 (m, 2H), 1.38 (d, J = 6.2 Hz, 6H),
1.24 (d, J = 6.2 Hz, 6H); 13C NMR (CDCl3, 75.45 MHz) d 151.3 (d,
JPCC = 9 Hz), 133.7 (d, JPCCCC = 2 Hz), 133.4 (d, JPCC = 7 Hz), 116.5 (d,
JPCCC = 14 Hz), 116.3 (d, JPCCC = 13 Hz), 109.3 (d, JPC = 184 Hz), 70.7
(d, JPOC = 5 Hz, 2C), 24.2 (d, JPOCC = 4 Hz, 2C), 23.8 (d, JPOCC = 5 Hz,
2C); 31P NMR (CDCl3, 121.47 MHz) d 20.2 (s); HRMS (EI+) Calc. for
4.4. Diisopropyl-4-pyridylphosphonate (Table 1, entry 3) [18]
C
12H20NO3P, (M)+ 257.1181. Found: 257.1178.
Yield: 63%. 1H NMR (CDCl3, 300 MHz) d 8.78–8.73 (m, 2H), 7.67
(dm, J = 12.9 Hz, 2H), 4.82–4.70 (m, 2H), 1.40 (d, J = 6.2 Hz, 6H),
1.27 (d, J = 6.2 Hz, 6H); 13C NMR (CDCl3, 75.45 MHz) d 150.1 (d,
JPCCC = 12 Hz, 2C), 139.1 (d, JPC = 187 Hz), 125.4 (d, JPCC = 8 Hz),
71.9 (d, JPOC = 6 Hz), 24.2 (d, JPOCC = 4 Hz), 24.0 (d, JPOCC = 4 Hz);
31P NMR (CDCl3, 121.47 MHz) d 13.5 (s).
4.10. Diisopropyl-3-anilinylphosphonate (Table 2, entry 2) [19]
Yield: 72%. M.p. 103–104 °C. 1H NMR (CDCl3, 300 MHz) d 7.28–
7.12 (m, 3H), 6.81 (d, J = 7.2 Hz, 1H), 4.71–4.60 (m, 2H), 3.86 (s, 2H,
NH2), 1.36 (d, J = 6.0 Hz, 6H), 1.22 (d, J = 6.3 Hz, 6H); 13C NMR
(CDCl3, 75.45 MHz)
d 146.9 (d, JPCCC = 18 Hz), 130.6 (d, JPC =
4.5. Diisopropyl-2-bromo-pyridyl-6-phosphonate (Table 1, entry 4)
190 Hz), 129.5 (d, JPCCC = 17 Hz), 121.3 (d, JPCC = 9 Hz), 118.6 (d,
JPCCCC = 3 Hz), 118.0 (d, JPCC = 12 Hz), 70.7 (d, JPOC = 5 Hz, 2C), 24.2
(d, JPOCC = 6 Hz, 2C), 24.0 (d, JPOCC = 5 Hz, 2C); 31P NMR (CDCl3,
121.47 MHz) d 18.5 (s).
After purification by column chromatography over silica gel, the
solid was recrystallized with hot hexanes. White crystal needles
were formed after cooling to room temperature and the crystals
were filtered and washed several times with cold hexanes. Yield:
4.11. Diisopropyl-4-anilinylphosphonate (Table 2, entry 3)
30%. M.p. 92–94 °C. 1H NMR (CDCl3, 300 MHz)
d 7.90 (t,
Yield: 70–92%. M.p. 113–115 °C. 1H NMR (CDCl3, 300 MHz) d
7.58 (dd, J = 12.9 Hz, J = 8.4 Hz, 2H), 6.67 (dd, J = 8.4 Hz, J = 3.3 Hz,
2H), 4.69–4.54 (m, 2H), 4.10 (s, 2H, NH2), 1.35 (d, J = 6.0 Hz, 6H),
J = 7.2 Hz, 1H), 7.66–7.55 (m, 2H), 4.92–4.76 (m, 2H), 1.39 (d,
J = 6.0 Hz, 6H), 1.31 (d, J = 6.3 Hz, 6H); 13C NMR (CDCl3,
75.45 MHz) d 154.7 (d, JPC = 227 Hz), 143.0 (d, JPCNC = 26 Hz),

3176
Y. Belabassi et al. / Journal of Organometallic Chemistry 693 (2008) 3171–3178
1.21 (d, J = 6.0 Hz, 6H); 13C NMR (CDCl3, 75.45 MHz) d 150.6, 133.7
(d, JPCC = 11 Hz, 2C), 117.1 (d, JPC = 198 Hz), 114.2 (d, JPCCC = 16 Hz,
2C), 70.3 (d, JPOC = 5 Hz, 2C), 24.3 (d, JPOCC = 4 Hz, 2C), 24.0 (d,
JPOCC = 5 Hz, 2C); 31P NMR (CDCl3, 121.47 MHz) d 19.1 (s); HRMS
(EI+) Calc. for C12H20NO3P, (M)+ 257.1181. Found: 257.1183.
2H), 1.40 (d, J = 6.3 Hz, 6H), 1.25 (d, J = 6.3 Hz, 6H); 13C NMR (CDCl3,
75.45 MHz) d 150.1(d, JPCCCC = 3 Hz), 137.4 (d, JPC = 188 Hz), 132.9
(d, JPCC = 11 Hz, 2C), 123.3 (d, JPCCC = 15 Hz, 2C), 71.8 (d, JPOC = 6 Hz,
2C), 24.1 (d, JPOCC = 4 Hz, 2C), 23.9 (d, JPOCC = 5 Hz, 2C); 31P NMR
(CDCl3, 121.47 MHz) d 13.9 (s).
4.12. Diisopropyl-[(3-tert-butoxycarbonylamino)phenyl]phosphonate
(Table 2, entry 4)
4.17. Diisopropyl-3-quinolinylphosphonate (Table 3, entry 4)
Yield: 46%. 1H NMR (CDCl3, 300 MHz) d 9.15 (dd, J = 4.5 Hz,
J = 1.8 Hz, 1H), 8.72 (dd, J = 15.0 Hz, J = 1.5 Hz, 1H), 8.16 (d,
J = 8.7 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.85 (dt, J = 7.2 Hz,
J = 1.5 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 4.84–4.72 (m, 2H), 1.43 (d,
J = 6.0 Hz, 6H), 1.26 (d, J = 6.0 Hz, 6H); 13C NMR (CDCl3,
75.45 MHz) d 151.1(d, JPCC = 12 Hz), 149.4, 142.9 (d, JPCC = 9 Hz),
131.9, 129.7 (d, JPCCCC = 1 Hz), 128.9, 127.7, 126.9 (d, JPCCC = 14 Hz),
123.6 (d, JPC = 189 Hz), 71.7 (d, JPOC = 5 Hz, 2C), 24.3 (d, JPOCC = 4 Hz,
2C), 24.1 (d, JPOCC = 5 Hz, 2C); 31P NMR (CDCl3, 121.47 MHz) d 19.3
(s); HRMS (EI+) Calc. for C15H20 NO3P, (M)+ 293.1181. Found:
293.1181.
After work-up, the solid was simply washed with Et2O, afford-
ing the desired product as a white powder. Yield: 81%. M.p. 168–
169 °C. 1H NMR (CDCl3, 300 MHz) d 7.82–7.78 (m, 1H), 7.62 (d,
J = 14.4 Hz, 1H), 7.48–7.37 (m, 2H), 6.78 (s, 1H, OH), 4.73–4.62
(m, 2H), 1.52 (s, 9H), 1.36 (d, J = 6.3 Hz, 6H), 1.22 (d, J = 6.3 Hz,
6H); 13C NMR (CDCl3, 75.45 MHz) d 152.9, 139.1 (d, JPCCC = 19 Hz),
130.1 (d, JPC = 189 Hz), 129.1 (d, JPCC = 16 Hz), 125.4 (d,
JPCCC = 9 Hz), 122.0 (d, JPCCCC = 1 Hz), 121.9 (d, JPCC = 8 Hz), 80.4,
70.7 (d, JPOC = 6 Hz, 2C), 28.3, 24.0 (d, JPOCC = 4 Hz, 2C), 23.8 (d,
JPOCC = 4 Hz, 2C); 31P NMR (CDCl3, 121.47 MHz) d 17.4 (s); HRMS
(EI+) Calc. for C17H28NO5P, (M)+ 357.1705. Found: 357.1696.
4.18. Diisopropyl-1-naphthylphosphonate (Table 3, entry 5)
4.13. Diisopropyl-[(4-tert-butoxycarbonylamino)phenyl]phosphonate
(Table 2, entry 5)
Yield: 86%. 1H NMR (CDCl3, 300 MHz) d 8.53 (d, J = 8.1 Hz, 1H),
8.30 (dd, J = 16.5 Hz, J = 6.9 Hz, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.87
(d, J = 8.1 Hz, 1H), 7.62–7.48 (m, 3H), 4.79–4.67 (m, 2H), 1.41 (d,
J = 6.3 Hz, 6H), 1.14 (d, J = 6.3 Hz, 6H); 13C NMR (CDCl3,
75.45 MHz) d 134.6 (d, JPCC = 9 Hz), 133.7 (d, JPCCC = 13 Hz), 133.5
(d, JPCCCC = 3 Hz), 132.8 (d, JPCCC = 11 Hz), 128.8 (d, JPCCCC = 1 Hz),
127.2, 127.1, 126.4, 126.3 (d, JPC = 183 Hz), 124.6 (d, JPCC = 17 Hz),
71.1 (d, JPOC = 5 Hz, 2C), 24.3 (d, JPOCC = 4 Hz, 2C), 23.9 (d,
JPOCC = 5 Hz, 2C); 31P NMR (CDCl3, 121.47 MHz) d 17.8 (s); HRMS
(EI+) Calc. for C16H21O3 P, (M)+ 292.1228. Found: 292.1124.
After purification by column chromatography over silica gel, the
solid was washed with petroleum ether, affording the pure product
as a white powder. Yield: 82%. 1H NMR (CDCl3, 300 MHz) d 7.73
(dd, J = 12.9 Hz, J = 8.7 Hz, 2H), 7.45 (dd, J = 8.4 Hz, J = 3.3 Hz, 2H),
6.67 (s, 1H, NH), 4.72–4.57 (m, 2H), 1.52 (s, 9H), 1.35 (d,
J = 6.3 Hz, 6H), 1.20 (d, J = 6.3 Hz, 6H); 13C NMR (CDCl3,
75.45 MHz) d 152.7, 142.5 (d, JPCCCC = 3 Hz), 133.1 (d, JPCC = 11 Hz,
2C), 123.3 (d, JPC = 194 Hz), 117.8 (d, JPCCCC = 15 Hz, 2C), 81.2, 70.7
(d, JPOC = 5 Hz, 2C), 28.5, 24.3 (d, JPOCC = 4 Hz, 2C), 24.0 (d,
JPOCC = 5 Hz, 2C); 31P NMR (CDCl3, 121.47 MHz) d 18.1 (s); HRMS
(EI+) Calc. for C17H28NO5P, (M)+ 357.1705. Found: 357.1710.
4.19. Diisopropyl-phenylphosphonate (Table 3, entry 6) [6,20]
Yield: 47–93%. 1H NMR (CDCl3, 300 MHz) d 7.82 (dd, J = 13.5 Hz,
J = 6.6 Hz, 2H), 7.53–7.49 (m, 1H), 7.47–7.40 (m, 2H), 4.75–4.63 (m,
2H), 1.37 (d, J = 6.6 Hz, 6H), 1.22 (d, J = 6.6 Hz, 6H); 13C NMR (CDCl3,
4.14. Diisopropyl-1,2-methylenedioxyphenyl-4-phosphonate (Table 3,
entry 1)
75.45 MHz)
d 132.1, 131.7 (d, JPCC = 10 Hz, 2C), 130.0 (d,
Yield: 99%. 1H NMR (CDCl3, 400 MHz) d 7.39 (ddd, J = 7.6 Hz,
J = 6.1 Hz, J = 1.4 Hz, 1H), 7.21 (dd, J = 12.9 Hz, J = 1.5 Hz, 1H), 6.87
(dd, J = 7.9 Hz, J = 3.5 Hz, 1H), 6.01 (s, 2H), 4.68–4.61 (m, 2H),
1.35 (d, J = 6.3 Hz, 6H), 1.22 (d, J = 6.2 Hz, 6H); 13C NMR (CDCl3,
JPC = 188 Hz), 128.4 (d, JPCCC = 15 Hz, 2C), 70.7 (2C), 24.1 (d,
JPOCC = 4 Hz, 2C), 23.8 (d, JPOCC = 5 Hz, 2C); 31P NMR (CDCl3,
121.47 MHz) d 17.6 (s).
75.45 MHz)
d
150.1(d, JPCCCC = 3 Hz), 147.8 (d, JPCCC = 22 Hz),
4.20. Diisopropyl-4-hydroxyphenylphosphonate (Table 3, entry 7)
127.2 (d, JPCC = 11 Hz), 122.9 (d, JPC = 194 Hz), 111.1 (d,
JPCC = 12 Hz), 108.4 (d, JPCCC = 19 Hz), 101.6, 70.6 (d, JPOC = 6 Hz,
2C), 24.0 (d, JPOCC = 4 Hz, 2C), 23.8 (d, JPOCC = 5 Hz, 2C); 13P NMR
(CDCl3, 121.47 MHz) d 17.8 (s); HRMS (EI+) calcd for C13H19O5P,
(M)+ 286.0970, found 286.0972.
Yield: 27–76%. M.p. 125–127 °C. 1H NMR (CDCl3, 300 MHz) d
9.79 (s, 1H, OH), 7.64 (dd, J = 12.9 Hz, J = 6.9 Hz, 2H), 7.02–6.99
(m, 2H), 4.71–4.56 (m, 2H), 1.36 (d, J = 6.3 Hz, 6H), 1.23 (d,
J = 6.3 Hz, 6H); 13C NMR (CDCl3, 75.45 MHz)
d 161.9 (d,
JPCCCC = 3 Hz), 133.9 (d, JPCC = 12 Hz, 2C), 117.9 (d, JPC = 198 Hz),
116.1 (d, JPCCC = 16 Hz, 2C), 71.2 (d, JPOC = 5 Hz, 2C), 24.2 (d,
JPOCC = 4 Hz, 2C), 24.0 (d, JPOCC = 4 Hz, 2C); 31P NMR (CDCl3,
121.47 MHz) d 19.9 (s); HRMS (EI+) Calc. for C12H19O4P, (M)+
258.1021. Found: 258.1022.
4.15. Diisopropyl-1,2,3-trimethoxyphenyl-5-phosphonate (Table 3,
entry 2)
Yield: 61%. M.p. 72–74 °C. 1H NMR (CDCl3, 300 MHz) d 7.00 (d,
J = 15.0 Hz, 2 H), 4.73–4.60 (m, 2H), 3.86 (s, 9H), 1.35 (d,
J = 6.3 Hz, 6H), 1.21 (d, J = 6.3 Hz, 6H); 13C NMR (CDCl3,
4.21. Diisopropyl-4-methylbenzoylphosphonate (Scheme 1, compound
75.45 MHz)
d
153.2 (d, JPCCC = 22 Hz, 3C), 141.3, 124.6 (d,
1)
JPC = 189 Hz), 108.9 (d, JPCC = 4 Hz), 108.8 (d, JPCC = 4 Hz), 70.9
(2C), 56.3 (3C), 24.2 (2C), 23.8 (2C); 31P NMR (CDCl3,
121.47 MHz) d 18.3 (s); HRMS (EI+) Calc. for C15H25O6P, (M)+
332.1389. Found: 332.1393.
Yield: 44%. 1H NMR (CDCl3, 300 MHz) d 8.14–8.09 (m, 2H),
7.94–7.86 (m, 2H), 4.77–4.66 (m, 2H), 3.95 (s, 3H), 1.38 (d,
J = 6.2 Hz, 6H), 1.23 (d, J = 6.2 Hz, 6H); 13C NMR (CDCl3,
75.45 MHz) d 166.4, 135.0 (d, JPC = 187 Hz), 133.4 (d, JPCCCC = 3 Hz),
131.8 (d, JPCC = 10 Hz, 2C), 129.4 (d, JPCCC = 15 Hz, 2C), 71.3 (d,
JPOC = 5 Hz, 2C), 52.5, 24.2 (d, JPOCC = 4 Hz, 2C), 23.9 (d, JPOCC = 5 Hz,
2C); 31P NMR (CDCl3, 36.441 MHz) d 14.7 (m); HRMS (EI+) Calc. for
4.16. Diisopropyl-4-nitrophenylphosphonate (Table 3, entry 3) [6,20]
Yield: 60%. 1H NMR (CDCl3, 300 MHz) d 8.30 (dd, J = 8.7 Hz,
J = 3.0 Hz, 2H), 8.01 (dd, J = 12.6 Hz, J = 8.4 Hz, 2H), 4.82–4.71 (m,
C
14H21O5P, (M)+ 300.1127. Found: 300.1120.

Y. Belabassi et al. / Journal of Organometallic Chemistry 693 (2008) 3171–3178
3177
4.22. Diisopropyl-4-cyanophenylphosphonate (Scheme 1, compound
2)
4.28. 3-Pyridine phosphonic acid (Scheme 2, compound 7)
[2d,14,22]Yield: 100%. M.p. 237–240 °C. 1H NMR (D2O, 300 MHz) d
8.84 (dd, J = 7, 1 Hz, 1H), 8.75 (dd, J = 7, 1 Hz, 1H), 8.71 (ddt, J = 12,
7, 1 Hz, 1H), 8.01–8.07 (m, 1H); 13C NMR (CDCl3, 75.45 MHz) d
148.4 (d, JPCC = 7 Hz), 142.37, 142.1 (d, JPCCC = 15 Hz), 136.5 (d,
JPC = 175 Hz), 127.5 (d, JPCC = 11 Hz); 31P NMR (D2O, 121.47 MHz)
d 4.48 (t, JPCCH = 9 Hz).
Yield: 57%. 1H NMR (CDCl3, 300 MHz) d 7.93 (dd, J = 12.9 Hz,
J = 7.8 Hz, 2H), 7.78–7.73 (m, 2H), 4.82–4.67 (m, 2H), 1.40 (d,
J = 6.3 Hz, 6H), 1.25 (d, J = 6.3 Hz, 6H); 13C NMR (CDCl3,
75.45 MHz) d 135.7 (d, JPC = 188 Hz), 132.4 (d, JPCC = 10 Hz, 2C),
132.1 (d, JPCCC = 15 Hz, 2C), 118.2, 115.9 (d, JPCCCC = 3 Hz), 71.8 (d,
JPOC = 6 Hz, 2C), 24.2 (d, JPOCC = 4 Hz, 2C), 24.1 (d, JPOCC = 5 Hz, 2C);
31P NMR (CDCl3, 36.441 MHz) d 14.2 (s); HRMS (EI+) Calc. for
Acknowledgments
C
13H18NO3P, (M)+ 267.1024. Found: 267.1025.
We gratefully acknowledge the National Institute of General
Medical Sciences/NIH (1R01 GM067610) for the financial support
of this research. We also thank TCU-SERC for S.A.’s partial support.
4.23. Diisopropyl-4-trifluorophenylphosphonate (Scheme 1, compound
3) [21]
Yield: 22%. 1H NMR (CDCl3, 300 MHz) d 7.95 (dd, J = 12.9 Hz,
J = 8.1 Hz, 2H), 7.74–7.70 (m, 2H), 4.80–4.68 (m, 2H), 1.40 (d,
J = 6.2 Hz, 6H), 1.25 (d, J = 6.2 Hz, 6H); 13C NMR (CDCl3,
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.jorganchem.2008.07.020.
75.45 MHz)
d 134.6 (d, JPC = 187 Hz), 133.9 (dq, JFC = 33 Hz,
JPCCCC = 3 Hz), 132.3 (d, JPCC = 10 Hz, 2C), 125.3 (d, JFC = 15 Hz,
4 Hz), 123.4 (d, JFC = 273 Hz), 71.5 (d, JPOC = 5 Hz), 24.2 (d,
JPOCC = 4 Hz), 24.0 (d, JPOCC = 5 Hz); 31P NMR (CDCl3, 36.441 MHz)
d 16.5 (s); 19F NMR (CDCl3, 282.306 MHz) d ꢁ63.7 (s).
References
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The crude reaction mixture from the Pd-catalyzed cross-cou-
pling was concentrated in vacuo. The residue was partitioned be-
tween concentrated aqueous HCl and CHCl3. The aqueous layer
was washed once with CHCl3, then treated with concentrated
aqueous NaOH. The resulting basic aqueous layer was extracted
with CHCl3 (3 X), and the combined organic layers dried with
MgSO4, and concentrated under reduced pressure. The resulting
oil was dissolved in CH2Cl2 and treated with bromotrimethylsilane
(2.2 equiv.) at room temperature under N2. When silylation was
complete (24–48 h, monitored by 31P NMR), the solvent was re-
moved in vacuo and MeOH was added. The phosphonic acids were
obtained as solids either directly, or by precipitation from water/
acetone or water/methanol.
4.25. Pyrazine phosphonic acid Scheme 2, compound 4)
Yield: 69%. M.p. 171–173 °C. 1H NMR (D2O, 300 MHz) d 8.63 (bs,
1H), 8.55 (bs, 1H), 8.45 (bs, 1H); 13C NMR (D2O, 75.45 MHz) d 152.1
(d, JPC = 206 Hz), 145.2 (d, JPCC = 16 Hz), 144.5, 144.2; 31P NMR
(D2O, 121.47 MHz) d 3.64 (s); HRMS (ES+) Calc. for C4H5N2O3P,
(M + H)+ 161.0116. Found: 161.0111.
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4.26. 5-Pyrimidine phosphonic acid (Scheme 2, compounds 5)
(t) D. Prim, J.-M. Campagne, D. Joseph, B. Andrioletti, Tetrahedron 58 (2002)
2041.
Yield: 78%. M.p. 203–204 °C. 1H NMR (D2O, 300 MHz) d (major,
PyrimP(O)(OH)2) 9.13 (s, 1H), 8.92 (d, J = 7 Hz, 2H), (minor,
PyrimH+P(O)(OH)(Oꢁ)) 8.09 (s, 1 H), 6.84 (d, J = 13 Hz, 1 H), 5.57
(d, J = 6 Hz, 1 H); 13C NMR (D2O, 75.45 MHz) d (major) 158.6 (d,
JPCC = 7 Hz), 155.7, 134.24 (d, JPC = 161 Hz); 31P NMR (D2O,
121.47 MHz) d (minor, PyrimH+P(O)(OH)(Oꢁ)) 9.34 (s) and (major,
PyrimP(O)(OH)2) 4.51 (s); HRMS (ES+) Calc. for C4H5N2O3P, (M +
H)+ 161.0116. Found: 161.0116.
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