Synthesis of aryl and arylmethyl phosphonates by cross-coupling of aryl or arylmethyl halides (X = I, Br and Cl) with diisopropyl H-phosphonate

Article abstract of DOI:10.1002/ejoc.201201230

An efficient and generally applicable protocol for the palladacycle- catalysed arylation or K₂CO₃-promoted arylmethylation of diisopropyl H-phosphonate has been developed. The remarkable features of the palladacycle-catalysed arylation reaction include wide substrate scope (aryl iodides, bromides and chlorides), significant shortening of the reaction time (2 or 3 h) and a low catalyst loading of 1 mol-%. Note that with the base K ₂CO₃ as promoter, arylmethylation could be achieved without any palladium catalyst. Moreover, the first example of a palladium-catalysed phosphonation of inactive electron-rich aryl chlorides with tBuOK as the base has been realized. This result could be considered an important improvement and complement to earlier work of Montchamp and Han, whose catalytic systems are typically compatible with electron-deficient and electron-neutral aryl chlorides.

Full text of DOI:10.1002/ejoc.201201230

FULL PAPER
DOI: 10.1002/ejoc.201201230
Synthesis of Aryl and Arylmethyl Phosphonates by Cross-Coupling of Aryl or
Arylmethyl Halides (X = I, Br and Cl) with Diisopropyl H-Phosphonate
Kai Xu,[a] Hao Hu,[a] Fan Yang,*[a] and Yangjie Wu*[a]
Keywords: Palladium / Cross-coupling / Halides / Phosphonates
An efficient and generally applicable protocol for the pallad-
acycle-catalysed arylation or K2CO3-promoted arylmethyl-
ation of diisopropyl H-phosphonate has been developed. The
remarkable features of the palladacycle-catalysed arylation
reaction include wide substrate scope (aryl iodides, bromides
and chlorides), significant shortening of the reaction time (2
or 3 h) and a low catalyst loading of 1 mol-%. Note that with
the base K2CO3 as promoter, arylmethylation could be
achieved without any palladium catalyst. Moreover, the first
example of a palladium-catalysed phosphonation of inactive
electron-rich aryl chlorides with tBuOK as the base has been
realized. This result could be considered an important im-
provement and complement to earlier work of Montchamp
and Han, whose catalytic systems are typically compatible
with electron-deficient and electron-neutral aryl chlorides.
catalytic system in the beginning of the 1980s.[2a,2b] Since
then, much research interest has been devoted to improving
the reaction conditions used by Gooßen,[2d] Stawin-
ski[2f–2h,2j,2l] and others,[2c,2e,2i,2k,2m–2p] for example, by vary-
ing the phosphane ligands (e.g., dppp, dppb, dppf and
Xantphos), organic (e.g., Et3N, Cy2NMe and iPr2NEt) or
inorganic (e.g., Cs2CO3, K2CO3 and K3PO4) bases, micro-
wave heating and palladium sources [e.g., Pd(PPh3)4,
Pd(OAc)2 and Pd/C]. In addition to the palladium catalyst,
other transition metals such as Cu[5] and Ni[6] could also
provide efficient access to phosphonated products from aryl
iodides or bromides. Nevertheless, all the above-mentioned
work was focused on the phosphonation of aryl iodides and
bromides. From the viewpoint of synthetic cost, phos-
phonation of the more commercially available aryl chlorides
would be a fascinating choice. In 2008, the first phos-
phonation of aryl chlorides was reported by Montchamp
and co-workers, albeit this catalytic system was effective for
electron-deficient aryl chlorides using 1 mol-% of Pd(OAc)2/
dppf as the catalyst.[2i] Just recently, Han and co-workers
also successfully carried out the cross-coupling reactions of
electron-neutral and -deficient aryl chlorides with dimethyl
H-phosphonate using 10 mol-% [NiCl2(dppp)] as the cata-
lyst.[6b]
On the other hand, the most common and versatile path-
way for the formation of sp3 C–P bonds is the reaction of
trialkyl phosphites (the Michaelis–Arbuzov reaction) or di-
alkyl phosphonates (the Michaelis–Becker reaction) with
alkyl halides,[3a–3m] which can proceed without any transi-
tion-metal catalyst and exhibit quite general substrate
scope. These reactions were performed at a higher tempera-
ture or with a base (e.g., NaH, Cs2CO3 and KHMDS),
respectively. Another type of approach is the transition-
metal-catalysed cross-coupling of alkyl halides with dialkyl
Introduction
Aryl and arylmethyl phosphonates have wide applica-
tions as valuable building blocks in organic synthetic, bio-
logical, pharmaceutical and materials sciences.[1] There are
two efficient synthetic protocols for the formation of the C–
P bond (Scheme 1). The first powerful approach to C–P
bond formation involves the direct cross-coupling of aryl or
alkyl halides with dialkyl H-phosphonates or trialkyl phos-
phites.[2,3] The second method involves the addition of H-
phosphonate to the triple bond of alkynes.[4]
Scheme 1. Typical C–P bond-forming protocols.
The pioneering work on palladium-catalysed phos-
phonation of aryl iodides or bromides belongs to Hirao and
co-workers, who introduced a dialkyl phosphonate moiety
at an sp2-hybridized carbon by using the [Pd(PPh3)4]/NEt3
[a] The College of Chemistry and Molecular Engineering, Henan
Key Laboratory of Chemical Biology and Organic Chemistry,
Key Laboratory of Applied Chemistry of Henan Universities,
Zhengzhou University,
Zhengzhou 450052, People’s Republic of China
Fax: +86-371-67979408
E-mail: yangf@zzu.edu.cn
wyj@zzu.edu.cn
Homepage: http://222.22.32.213/hxx/cn/Shownews.asp?ID=325
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201230.
Eur. J. Org. Chem. 2013, 319–325
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
319

K. Xu, H. Hu, F. Yang, Y. Wu
FULL PAPER
H-phosphonates.[3n–3q] In the development of these two Table 1. Effects of bases and solvents on the reaction of 4-bromo-
toluene with diisopropyl H-phosphonate.[a]
types of phosphonations of arylmethyl halides, significant
progress has been achieved by Rousseau,[3e] Salvatore,[3c]
Zografos[3h] and Stawinski[3p] and their co-workers.
Cyclopalladated ferrocenylimines as a family of versatile
palladacyclic catalysts (Figure 1), which were discovered
and developed by our research group, have been success-
fully applied to various catalytic reactions.[7] Inspired by the
above promising reports and our own work, we have fo-
cused our research interest on the possible palladacycle-cat-
alysed cross-coupling of aryl halides or arylmethyl halides
with diisopropyl H-phosphonate, especially for the reaction
of inactive electron-rich and -neutral aryl chlorides. In ad-
dition, the need for a metal catalyst will also be discussed
in the cross-coupling of arylmethyl halides with diisopropyl
H-phosphonate.
Entry
Catalyst
Base
Solvent Yield [%][b]
1
2
3
4
5
6
Palladacycle II
Palladacycle II
Palladacycle II
Palladacycle II
Palladacycle II
Palladacycle II
Palladacycle II
Palladacycle II
–
Palladacycle II
Palladacycle I/PPh3
Pd(OAc)2/PPh3
NiCl2/PPh3
Na2CO3 DMF
48
40
24
95 (91)
90 (85)
12
K3PO4
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
DMF
DMA
THF
7[c]
8[d]
9
DMF
DMF
DMF
DMF
DMF
DMF
DMF
35
73
Ͻ5
31
92
81
Ͻ5
10[e]
11[f]
12[g]
13[h]
[a] Reagents and conditions: 4-bromotoluene (0.4 mmol), di-
isopropyl H-phosphonate (0.6 mmol), base (1.2 mmol) and the pal-
ladacycle II (1 mol-%) in solvent (2 mL) at 100 °C under nitrogen
for 2 h. [b] GC yield (isolated yield) based on the amount of 4-
bromotoluene. [c] Using 0.5 mol-% of the palladacycle II. [d] Under
air. [e] At 80 °C. [f] Palladacycle I (0.5 mol-%), PPh3 (1 mol-%). [g]
Pd(OAc)2 (2 mol-%), PPh3 (2 mol-%). [h] NiCl2 (2 mol-%), PPh3
(2 mol-%).
Figure 1. Cyclopalladated ferrocenylimines.
The substrate scope for the reaction was then investi-
gated under the optimized reaction conditions (Table 2). In
general, electronic effects had no significant influence on
the phosphonation of aryl iodides and bromides, affording
the desired products in moderate-to-good yields (Table 2,
entries 1–13). Note that the reactions of heteroaryl brom-
ides such as 5-bromobenzothiophene (1g) and 3-bromopyr-
idine (1n) also gave the phosphonated products in 97 and
77% isolated yields, respectively (Table 2, entries 6 and 13).
Moreover, the reaction could also tolerate aryl halides bear-
ing a sterically hindered ortho substituent except for 1-
bromo-2-methylnaphthalene (1f; Table 2, entries 1, 3 and 5).
Results and Discussion
Palladacycle-Catalysed Phosphonation of Aryl Iodides and
Bromides
In our initial study, we examined the effects of bases and
solvents on the reaction of 4-bromotoluene with di-
isopropyl H-phosphonate (Table 1). The reaction was first
performed with Na2CO3 as the base in DMF under nitro-
gen, and a relatively low yield of 48% was observed by GC
(Table 1, entry 1). Other bases were employed in this reac-
tion and K2CO3 was found to give the best result with a
GC yield of 95% and an isolated yield of 91% (Table 1,
entries 2–4). Then the effect of aprotic polar solvents was
also explored (Table 1, entries 5 and 6). For example, N,N-
dimethylacetamide (DMA) as solvent also afforded the cou-
Palladacycle-Catalysed Phosphonation of Aryl Chlorides
Subsequently we performed a similar optimization pro-
pling product in a GC yield of 90% (Table 1, entry 5) but cess for the palladacycle I catalysed phosphonation of aryl
THF did not exhibit a comparably favourable result chlorides, and the effects of ligands and bases were screened
(Table 1, entry 6). However, a decrease in the catalyst load- (Table 3). The use of commercially available phosphane li-
ing or temperature, the absence of catalyst or performing gands (Figure 2) such as 1,2-bis(diphenylphosphanyl)eth-
the reaction in air in place of nitrogen resulted in a lower ane (dppe), 1,1Ј-bis(diphenylphosphanyl)ferrocene (dppf),
or even no yield at all (Table 1, entries 7–10). Note that the 2-dicyclohexylphosphanyl-2Ј-(dimethylamino)biphenyl
combination of palladacycle I and PPh3 gave the phos- (Davephos) and 2-(dicyclohexylphosphanyl)-2Ј,4Ј,6Ј-tri-
phonated product in a yield of 92%, which is a similar yield isopropyl-1,1Ј-biphenyl (X-phos) were first examined in the
to that obtained with palladacycle II (Table 1, entry 11). presence of the strong base tBuOK in DMA; X-phos was
Some commercially available metal catalysts were also found to be the best ligand and gave the product in nearly
evaluated; Pd(OAc)2 gave a satisfactory yield of 81%, quantitative yield (Table 3, entries 1–4). Other bases (e.g.,
whereas NiCl2 did not show any catalytic activity at all tBuONa, Cs2CO3 and CsF) did not exhibit satisfactory ac-
(Table 1, entries 12 and 13).
tivity (Table 3, entries 5–7). Commercially available Pd or
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Synthesis of Aryl and Arylmethyl Phosphonates
Table 2. Cross-coupling reactions of aryl iodides and bromides with
diisopropyl H-phosphonate.[a]
Table 3. Effects of ligands and bases on the reaction of 4-chloro-
anisole with diisopropyl H-phosphonate.[a]
Entry Catalyst
Ligand
Base
Yield [%][b]
1
2
3
4
5
6
7
Palladacycle I
Davephos
dppf
dppe
tBuOK
tBuOK
tBuOK
tBuOK
tBuONa
Cs2CO3
CsF
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
57
37
29
99 (99)
57
15
NR
23
77
85
Ͻ5
Ͻ5
Palladacycle I
Palladacycle I
Palladacycle I
Palladacycle I
Palladacycle I
Palladacycle I
Pd(OAc)2
[Pd{P(C6H11)3}2Cl2]
[Pd2(dba)3]
NiCl2
X-phos
X-phos
X-phos
X-phos
X-phos
–
X-phos
X-phos
–
8[c]
9[d]
10[e]
11[f]
12[g]
[NiCl2(dppe)]
[a] Reagents and conditions: 4-chloroanisole (0.4 mmol), di-
isopropyl H-phosphonate (0.6 mmol), base (1.2 mmol), palladacy-
cle I (1 mol-%) and phosphane ligand (4 mol-%) in DMA (2 mL)
at 130 °C under nitrogen for 3 h. [b] GC yield (isolated yield) based
on the amount of 4-chloroanisole. [c] Using 2 mol-% of
Pd(OAc)2 and 4 mol-% of X-phos as the catalyst. [d] Using 2 mol-
% of [Pd{P(C6H11)3}2Cl2] as the catalyst. [e] Using 2 mol-% of
[Pd2(dba)3] and 4 mol-% of X-phos as the catalyst. [f] Using 2 mol-
% of NiCl2 and 4 mol-% of X-phos as the catalyst. [g] Using 2 mol-
% of [NiCl2(dppe)] as the catalyst.
Figure 2. Phosphane ligands used in the screening of the pallada-
cycle I catalysed phosphonation of aryl chlorides.
With the optimized conditions in hand, the scope of the
aryl chlorides was investigated and selected results are sum-
marized in Table 4. In general, the catalytic system was ap-
plicable to electron-rich and -neutral aryl chlorides, and the
desired products were obtained in moderate-to-good yields
[a] Reagents and conditions: aryl halide (0.4 mmol), diisopropyl H-
phosphonate (0.6 mmol), K2CO3 (1.2 mmol) and the palladacycle
II (1 mol-%) in DMF (2 mL) at 100 °C under nitrogen for 2 h. [b]
Isolated yield based on the amount of aryl halide. [c] After 24 h.
Ni catalysts {e.g., Pd(OAc)2, [Pd{P(C6H11)3}2Cl2], (Table 4, entries 1–5). Notably, the reaction of 3-chlorotolu-
[Pd2(Pda)3], NiCl2 and [NiCl2(dppe)]} did not give satisfac- ene (1q) with diisopropyl H-phosphonate (2a) afforded the
tory results, which demonstrates that the palladacycle in- product in a yield of 99% (Table 4, entry 2). However, the
deed has an advantage over simple metal salts (Table 3, en- electron-deficient heterocyclic chloride (1u) was phos-
tries 8–12).
phonated in a low yield of only 26% (Table 4, entry 6).
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K. Xu, H. Hu, F. Yang, Y. Wu
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Table 4. Cross-coupling reactions of aryl chlorides with diisopropyl
H-phosphonate.[a]
Table 5. Effect of base on the reaction of benzyl bromide with di-
isopropyl H-phosphonate.[a]
Entry
Base
Solvent
Yield [%][b]
1[c]
2
3
4
5
Cs2CO3
Cs2CO3
Na2CO3
KHCO3
K3PO4
KF·2H2O
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMF
DMF
dioxane
toluene
99
99
Ͻ5
56
92
Ͻ5
97
68
30
Ͻ5
25
17
6
7
8[d]
9
10
11
12
[a] Reagents and conditions: benzyl bromide (0.4 mmol), di-
isopropyl H-phosphonate (0.6 mmol) and base (0.6 mmol) in DMA
(2 mL) at 120 °C under nitrogen for 3 h. [b] GC yield (isolated
yield) based on the amount of benzyl bromide. [c] Using 1 mol-%
palladacycle II. [d] Under air.
Table 6. Cross-coupling reactions of arylmethyl halides with di-
isopropyl H-phosphonate.[a]
[a] Reagents and conditions: aryl chloride (0.4 mmol), diisopropyl
H-phosphonate (0.6 mmol), tBuOK (1.2 mmol), palladacycle I
(1 mol-%) and X-phos (4 mol-%) in DMA (2 mL) at 130 °C under
nitrogen for 3 h. [b] Isolated yield based on the amount of aryl
chloride.
Base-Promoted Arylmethylation of H-Phosphonate
We performed a similar optimization process for the pal-
ladacycle-catalysed phosphonation of arylmethyl halides
and found that palladacycle II gave a high yield of 99%
with Cs2CO3 as the base in DMA (Table 5, entry 1). How-
ever, in the absence of the palladacycle, the reaction also
proceeded smoothly, giving the same yield of 99% (Table 5,
entry 2). This suggests that the metal is not indispensable
in this reaction and it prompted us to explore the aryl-
methylation of H-phosphonate under metal-free conditions.
After extensive screening of a variety of bases and solvent,
the optimal reaction conditions were found to be as follows:
K2CO3 (1.5 equiv.) in DMA (2.0 mL) at 120 °C under nitro-
gen (Table 5, entry 7). Under these conditions, the reactions
of electron-neutral and -rich benzyl bromides (4a and 4b)
proceeded smoothly, affording the corresponding products
in nearly quantitative yields (Table 6, entries 1 and 2).
[a] Reagents and conditions: arylmethyl halide (0.4 mmol), di-
isopropyl H-phosphonate (0.6 mmol) and K2CO3 (0.6 mmol) in
DMA (2 mL) under nitrogen for 3 h. [b] Isolated yield based on
the amount of arylmethyl halide.
Chemoselective Phosphonation of the sp2 or sp3 C–X Bond
Finally, the chemoselective phosphonation of the sp2 or
Moreover, the reaction protocol was also tolerant of elec- sp3 C–X bond was investigated by using 4-chlorobenzyl
tron-deficient 4-bromobenzyl bromide (4c), naphthylmethyl bromide as the starting material (Scheme 2). We found that
bromide (4d) and benzyl chloride (4e), affording the phos- the reaction of the sp3 C–X bond proceeded smoothly and
phonated products in good yields (Table 6, entries 3–5).
chemoselectively to generate the corresponding product in
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Synthesis of Aryl and Arylmethyl Phosphonates
Scheme 2. Chemoselective phosphonation of the 4-chlorobenzyl bromide.
a yield of 93%; reaction of the sp2 C–X bond afforded the
product in 53% yield, albeit accompanied by alkoxylation
of the sp3 C–X bond.
of Celite and washed with ethyl acetate. The mixture was added to
H2O (25 mL) and extracted with ethyl acetate (3ϫ 10 mL). The
combined organic layers were dried with anhydrous Na2SO4 and
filtered. After removal of the solvent in vacuo, the residue was puri-
fied by flash chromatography on silica gel (ethyl acetate/hexane) to
give the pure product.
Conclusions
Phosphonation of Arylmethyl Halides: Arylmethyl halide
(0.4 mmol), diisopropyl H-phosphonate (0.6 mmol) and K2CO3
(0.6 mmol) were dissolved in DMA (2 mL) in a 10 mL vial under
nitrogen. The reaction was carried out at 120 °C for 3 h. After com-
pletion of the reaction, the mixture was filtered through a pad of
Celite and washed with ethyl acetate. The mixture was added to
H2O (25 mL) and extracted with ethyl acetate (3ϫ 10 mL). The
combined organic layers were dried with anhydrous Na2SO4 and
filtered. After removal of the solvent in vacuo, the residue was puri-
fied by flash chromatography on silica gel (ethyl acetate/hexane) to
give the pure product.
Diisopropyl (2-Acetamidophenyl)phosphonate (3b): Yield 88%. 1H
NMR (400 MHz, CDCl3): δ = 10.69 (s, 1 H), 8.58 (t, J = 7.2 Hz,
1 H), 7.61–7.48 (m, 2 H), 7.11 (t, J = 5.6 Hz, 1 H), 4.69–4.61 (m,
2 H), 2.21 (s, 3 H), 1.39 (d, J = 6.0 Hz, 6 H), 1.23 (d, J = 6.0 Hz,
6 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 169.0, 142.4 (d, J =
7.5 Hz), 133.7 (d, J = 2.2 Hz), 132.6 (d, J = 5.7 Hz), 122.8 (d, J =
13.6 Hz), 120.6 (d, J = 11.4 Hz), 115.1 (d, J = 179.1 Hz), 71.6 (d,
J = 5.4 Hz), 25.2, 24.0 (d, J = 3.8 Hz), 23.7 (d, J = 5.0 Hz) ppm.
31P NMR (CDCl3, 163 MHz): δ = 17.9 ppm. HRMS: calcd. for
C14H23NO4P+ [M + H]+ 300.1365; found 300.1365.
We have developed efficient catalytic systems for the pal-
ladacycle (cyclopalladated ferrocenylimines) catalysed
phosphonation of aryl iodides, bromides and chlorides. In
these reactions, the palladacycles have shown higher cata-
lytic activity than commercially available palladium or
nickel salts. The phosphonation of aryl chlorides provides
the first successful examples of the cross-coupling of inac-
tive electron-donating aryl chlorides with diisopropyl H-
phosphonates. In addition, the phosphonation of arylme-
thyl bromides and chlorides was also realized by using the
cheaper base K2CO3 as the promoter. Current studies are
focused on further exploration of the substrate scope and
synthetic applications of these methodologies.
Experimental Section
General: 1H, 13C and 31P NMR spectra were recorded with a
Bruker DPX-400 spectrometer with CDCl3 as the solvent and TMS
as the internal standard. Melting points were measured with a WC-
1 microscopic apparatus. GC analysis was performed with an Ag-
ilent 4890D gas chromatograph. Mass spectra were recorded with
an LC-MSD-Trap-XCT instrument. HRMS were recorded with a
MALDI-FTMS spectrometer. Ethyl acetate and hexane (analytical
grade) were used as eluents for column chromatography without
purification. Other solvents were purified according to the standard
methods. The cyclopalladated ferrocenylimines were synthesized
according to the literature.[8] Other chemicals were bought from
commercial sources and used as received unless otherwise noted.
Diisopropyl (2-Methylnaphthalen-1-yl)phosphonate (3f): Yield 40%.
1H NMR (400 MHz, CDCl3): δ = 9.07 (d, J = 8.8 Hz, 1 H), 7.86
(d, J = 8.4 Hz, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.53 (t, J = 7.8 Hz,
1 H), 7.44 (t, J = 7.4 Hz, 1 H), 7.35–7.31 (m, 1 H), 4.78–4.69 (m,
2 H), 2.89 (s, 3 H), 1.42 (d, J = 6.4 Hz, 6 H), 1.11 (d, J = 6.0 Hz,
6 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 143.4 (d, J =
10.5 Hz), 133.5 (d, J = 12.7 Hz), 131.6 (d, J = 3.3 Hz), 131.0 (d, J
= 12.9 Hz), 129.1 (d, J = 17.3 Hz), 127.2, 126.5 (d, J = 2.9 Hz),
125.8, 124.1, 122.1 (d, J = 177.8 Hz), 69.5 (d, J = 5.2 Hz), 23.1 (d,
J = 3.9 Hz), 22.9 (d, J = 3.2 Hz), 22.7 (d, J = 4.8 Hz) ppm. 31P
NMR (CDCl3, 163 MHz): δ = 17.5 ppm. HRMS: calcd. for
C14H24O3P+ [M + H]+ 307.1463; found 307.1464.
Diisopropyl (Benzo[b]thiophen-5-yl)phosphonate (3g): Yield 97%. 1H
NMR (400 MHz, CDCl3): δ = 8.37 (d, J = 14.5 Hz, 1 H), 7.97 (dd,
J = 8.3, 3.4 Hz, 1 H), 7.74 (dd, J = 12.0, 8.4 Hz, 1 H), 7.54 (d, J
= 5.2 Hz, 1 H), 7.43 (d, J = 5.6 Hz, 1 H), 4.79–4.67 (m, 2 H), 1.41
(d, J = 6.0 Hz, 6 H), 1.24 (d, J = 6.0 Hz, 6 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 143.3 (d, J = 3.0 Hz), 139.1 (d, J =
17.1 Hz), 128.1 (d, J = 10.8 Hz), 127.6, 126.3 (d, J = 10.9 Hz),
125.6 (d, J = 188.7 Hz), 124.2, 122.6 (d, J = 15.8 Hz), 70.7 (d, J =
5.4 Hz), 24.1 (d, J = 3.8 Hz), 23.9 (d, J = 4.8 Hz) ppm. 31P NMR
(CDCl3, 163 MHz): δ = 18.0 ppm. HRMS: calcd. for C14H20O3PS+
[M + H]+ 299.0871; found 299.0871.
Palladacycle-Catalysed Phosphonation of Aryl Iodides and Brom-
ides: Aryl iodide or bromide (0.4 mmol), diisopropyl H-phos-
phonate (0.6 mmol), K2CO3 (1.2 mmol) and palladacycle II (1 mol-
%) were dissolved in DMF (2 mL) in a 10 mL vial under nitrogen.
The reaction was carried out at 100 °C for 2 h. After completion
of the reaction, the mixture was filtered through a pad of Celite
and washed with ethyl acetate. The mixture was added to H2O
(25 mL) and extracted with ethyl acetate (3ϫ 10 mL). The com-
bined organic layer was dried with anhydrous Na2SO4 and filtered.
After removal of the solvent in vacuo, the residue was purified by
flash chromatography on silica gel (ethyl acetate/hexane) to give
the pure product.
Palladacycle-Catalysed Phosphonation of Aryl Chlorides: A mixture
of aryl chloride (0.4 mmol), diisopropyl H-phosphonate
1
(0.6 mmol), KOtBu (1.2 mmol) and palladacycle I (1 mol-%)/X- Diisopropyl (4-Vinylphenyl)phosphonate (3h): Yield 99%. H NMR
phos (4 mol-%) was dissolved in DMA (2 mL) in a 10 mL vial un-
der nitrogen. The reaction was carried out at 130 °C for 3 h. After
completion of the reaction, the mixture was filtered through a pad
(400 MHz, CDCl3): δ = 7.77 (dd, J = 13.2, 8.0 Hz, 2 H), 7.47 (dd,
J = 8.1, 3.8 Hz, 2 H), 6.73 (dd, J = 17.6, 10.8 Hz, 1 H), 5.85 (d, J
= 17.6 Hz, 1 H), 5.36 (d, J = 10.8 Hz, 1 H), 4.73–4.63 (m, 2 H),
Eur. J. Org. Chem. 2013, 319–325
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K. Xu, H. Hu, F. Yang, Y. Wu
1.37 (d, J = 6.0 Hz, 6 H), 1.22 (d, J = 6.4 Hz, 6 H) ppm. 13C NMR 130.1 (d, J = 9.0 Hz), 119.7 (d, J = 4.6 Hz), 69.7 (d, J = 6.9 Hz),
FULL PAPER
(CDCl3, 100 MHz): δ = 141.1 (d, J = 3.1 Hz), 136.0, 132.0 (d, J =
10.1 Hz), 129.0 (d, J = 189.1 Hz), 126.0 (d, J = 15.3 Hz), 116.3,
33.3 (d, J = 139.2 Hz), 23.0 (d, J = 3.8 Hz), 22.8 (d, J =
5.0 Hz) ppm. 31P NMR (CDCl3, 163 MHz): δ = 24.0 ppm. HRMS:
70.7 (d, J = 5.4 Hz), 24.0 (d, J = 3.9 Hz), 23.8 (d, J = 4.8 Hz) ppm. calcd. for C13H21ClO3P+ [M + H]+ 335.0412; found 335.0412.
31P NMR (CDCl3, 163 MHz): δ = 17.0 ppm. HRMS: calcd. for
Diisopropyl (Naphthalen-1-ylmethyl)phosphonate (5d): Yield 86%.
C14H22O3P+ [M + H]+ 269.1307; found 269.1310.
1H NMR (400 MHz, CDCl3): δ = 8.14 (d, J = 8.4 Hz, 1 H), 7.84
(d, J = 8.0 Hz, 1 H), 7.77 (dd, J = 7.8, 0.6 Hz, 1 H), 7.57–7.41 (m,
4 H), 4.62–4.53 (m, 2 H), 3.61 (d, J = 22.0 Hz, 2 H), 1.25 (d, J =
6.0 Hz, 6 H), 1.04 (d, J = 6.0 Hz, 6 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 133.8 (d, J = 2.6 Hz), 132.1 (d, J = 5.2 Hz), 128.5,
128.5, 128.4, 127.5 (d, J = 4.2 Hz), 125.9, 125.7, 125.3 (d, J =
4.1 Hz), 124.7 (d, J = 1.6 Hz), 70.7 (d, J = 7.1 Hz), 31.7 (d, J =
139.9 Hz), 24.1 (d, J = 3.6 Hz), 23.7 (d, J = 5.2 Hz) ppm. 31P NMR
(CDCl3, 163 MHz): δ = 25.0 ppm. HRMS: calcd. for C17H24O3P+
[M + H]+ 307.1464; found 307.1464.
Diisopropyl (4-Methoxycarbonylphenyl)phosphonate (3k): Yield
1
95%. H NMR (400 MHz, CDCl3): δ = 8.11 (dd, J = 8.0, 3.6 Hz,
2 H), 7.90 (dd, J = 13.0, 8.2 Hz, 2 H), 4.77–4.67 (m, 2 H), 3.95 (s,
3 H), 1.38 (d, J = 6.0 Hz, 6 H), 1.23 (d, J = 6.0 Hz, 6 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 166.3, 134.9 (d, J = 186.1 Hz), 133.2
(d, J = 3.2 Hz), 131.7 (d, J = 9.9 Hz), 129.3 (d, J = 14.9 Hz), 71.2
(d, J = 5.6 Hz), 52.4, 24.0 (d, J = 4.0 Hz), 23.8 (d, J = 4.7 Hz) ppm.
31P NMR (CDCl3, 163 MHz): δ = 15.1 ppm. HRMS: calcd. for
C14H22O5P+ [M + H]+ 301.1199; found 301.1206.
Diisopropyl (4-Chlorobenzyl)phosphonate (5e): Yield 93%. 1H
NMR (400 MHz, CDCl3): δ = 7.29–7.21 (m, 4 H), 4.65–4.56 (m, 2
H), 3.06 (d, J = 21.6 Hz, 2 H), 1.27 (d, J = 6.0 Hz, 6 H), 1.17 (d,
J = 6.4 Hz, 6 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 132.6 (d,
J = 4.3 Hz), 131.2 (d, J = 6.6 Hz), 130.6 (d, J = 9.1 Hz), 128.5 (d,
J = 3.0 Hz), 70.7 (d, J = 6.9 Hz), 34.1 (d, J = 139.2 Hz), 24.0 (d, J
= 3.7 Hz), 23.8 (d, J = 4.9 Hz) ppm. 31P NMR (CDCl3, 163 MHz):
δ = 24.3 ppm. HRMS: calcd. for C13H21ClO3P+ [M + H]+
291.0917; found 291.0917.
Diisopropyl (2-Chlorophenyl)phosphonate (3l): Yield 66%. 1H NMR
(400 MHz, CDCl3): δ = 8.05 (dd, J = 14.4, 7.2 Hz, 1 H), 7.47–7.44
(m, 2 H), 7.38–7.27 (m, 1 H), 4.78–4.69 (m, 2 H), 1.40 (d, J =
6.0 Hz, 6 H), 1.26 (d, J = 6.4 Hz, 6 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 136.8 (d, J = 2.8 Hz), 136.0 (d, J = 8.0 Hz), 133.3
(d, J = 2.5 Hz), 130.7 (d, J = 10.1 Hz), 128.5 (d, J = 189.1 Hz),
126.3 (d, J = 13.7 Hz), 71.4 (d, J = 5.6 Hz), 24.1 (d, J = 4.1 Hz),
23.7 (d, J = 4.8 Hz) ppm. 31P NMR (CDCl3, 163 MHz): δ =
12.5 ppm. HRMS: calcd. for C14H22O5P+ [M + H]+ 277.0760;
found 277.0762.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization data, and 1H, 13C
and 31P NMR spectra for all products.
Diisopropyl (4-Acetamidophenyl)phosphonate (3o): Yield 54%. 1H
NMR (400 MHz, CDCl3): δ = 9.26 (s, 1 H), 7.74–7.70 (m, 4 H),
4.68–4.59 (m, 2 H), 2.19 (s, 3 H), 1.35 (d, J = 6.4 Hz, 6 H), 1.22
(d, J = 6.0 Hz, 6 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 169.4,
142.5 (d, J = 3.4 Hz), 132.7 (d, J = 10.7 Hz), 123.7 (d, J =
192.2 Hz), 119.0 (d, J = 15.2 Hz), 70.8 (d, J = 5.4 Hz), 24.5, 24.0
(d, J = 3.9 Hz), 23.8 (d, J = 4.8 Hz) ppm. 31P NMR (CDCl3,
163 MHz): δ = 17.2 ppm. 31P NMR (CDCl3, 163 MHz): δ =
17.2 ppm. HRMS: calcd. for C14H23NO4P+ [M + H]+ 300.1365;
found 300.1365.
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (NSFC) (grant numbers 21172200 and 21102134) and the
Innovation Fund for Outstanding Scholars of Henan Province
(grant number 621001100) for financial support to this research.
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1
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H), 6.93–6.83 (m, 2 H), 4.65–4.56 (m, 2 H), 3.82 (s, 3 H), 3.21 (d,
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Received: September 14, 2012
Published Online: November 20, 2012
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