Palladium-catalyzed direct phosphonation of azoles with dialkyl phosphites

Article abstract of DOI:10.1039/c2cc30429e

The first Pd-catalyzed direct phosphonation of azoles with dialkyl phosphites has been achieved without addition of base or acid. This method involves the oxidative cleavage of C-H and P(O)-H bonds and represents an atom-efficiency alternative to the classical phosphonation of Ar-X. A Pd ^II/Pd^IV mechanism has been studied and proposed.

Full text of DOI:10.1039/c2cc30429e

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COMMUNICATION
Palladium-catalyzed direct phosphonation of azoles with dialkyl
phosphitesw
Chaodong Hou,ab Yunlai Ren, Rui Lang, Xiaoxue Hu, Chungu Xia and Fuwei Li*
b
a
a
a
a
Received 18th January 2012, Accepted 5th April 2012
DOI: 10.1039/c2cc30429e
2
the C(sp )–P bond formation through direct phosphonation
The first Pd-catalyzed direct phosphonation of azoles with
dialkyl phosphites has been achieved without addition of base
or acid. This method involves the oxidative cleavage of C–H and
P(O)–H bonds and represents an atom-efficiency alternative to
of the aryl C–H bond with phosphite ester. Pursuing our
8
interest in the functionalization of heterocycles, we herein report
the first example of the catalytically oxidative phosphonation of
the heterocyclic aryl C–H bond without addition of any base or
acid (path II).
II
IV
the classical phosphonation of Ar–X. A Pd /Pd mechanism
has been studied and proposed.
During the past decade, great efforts have been devoted to the
direct C(2)–H functionalizations of azoles to yield 2-substituted
Aryl phosphonates and their derivatives have found a wide range
of applications in medicinal chemistry, catalysis and organic
9
azoles. In this context, their arylation, alkynylation, alkylation,
10
11
1
carboxylation, carbonylation and amination have been
2a
12b
13
1
synthesis. Since the pioneering work developed by Hirao and
2
3
co-workers in 1981, transition metal catalyzed cross-coupling of
successfully achieved. However, the transition metal catalyzed
14,15
direct 2-phosphonation of azoles has not yet been discovered.
4
aryl halides, triflates, tosylates, diazonium salts and boronic
5a
5b
5c
5d
We initiated this unprecedented study by screening the
optimized conditions in the model oxidative phosphonation
of benzothiazole (1a) with diethyl phosphite (2a) (Table 1 and
Tables S1–S4 in the ESIw). Although the reaction proceeded
slowly, we were glad to find that only the C-2 phosphonated
acids with dialkyl phosphites has become one of the most
2
straightforward routes to construct C(sp )–P bonds (Scheme 1,
path I). However, classical phosphonation methodologies would
require the prefunctionalization of Ar–H and normally the use
of a stoichiometric amount of base. In 2006, Ishii et al. reported
a radical phosphonation of benzene derivatives with diethyl
product (3a) was obtained in CH
3
CN catalyzed by 5 mol%
6a
Pd(OAc) in the presence of K S O at 100 1C (entry 1). In
phosphite, affording arylphosphonates with low regioselectivity.
2
2
2
8
III
Later on, Zou and Zhang developed another similar Mn
promoting radical phosphonation of heterocycles in the presence
2007, Fu and co-workers reported that proline (L1) could be
employed as a ligand to enhance the efficiency of copper-
1
6
6b
catalyzed addition of P(O)H compounds to alkynes. To our
delight, introducing L1 could significantly increase the yield of
the desired 3a from 12% to 56% (entry 3) and enhancement of
the amount of L1 (50 mol%) could not increase the catalytic
of 3.0 equiv. of Mn(OAc) with respect to the aryl substrates.
3
It is important to note that these two radical methods need
aliphatic acid as solvent to achieve the optimized reactivity.
Recently, transition metal catalyzed aromatic C–H functionali-
zations have found increasing applications in the formation of
performance further (entry 4). Replacing Pd(OAc)
2
with other
2
(COD) gave
7
Pd-containing resources such as Pd(TFA) and PdCl
2
C–C and C–heteroatom bonds. However, to the best of our
rise to the slight reduction of the product output (entries 5–7),
suggesting that the counter-ion of the Pd catalyst may not be the
decisive factor for the catalytic efficiency, which is different to the
Pd-catalyzed phosphonation between aryl halide and dialkyl
knowledge, there are scarce catalytic examples regarding
4
d
phosphite. The same yield of 3a was achieved when the
experiment was performed under argon instead of air, however,
carrying out reaction under a pure oxygen atmosphere dramati-
cally slowed down the phosphonation, only affording 3a in 10%
yield (Table 1, entries 8 and 9). 100 1C gave the best result and
either increasing or reducing the temperature would result in a
lower yield of the desired product (entries 10 and 11). Although
the phosphonation was not complete within 24 h, prolonging
the reaction time to 30 h could not improve the catalytic
performance further (entry 12).
Scheme 1 Transition metal catalyzed phosphonation reaction.
a
State Key Laboratory for Oxo Synthesis and Selective Oxidation,
Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou, 730000, China. E-mail: fuweili@licp.cas.cn;
Fax: +86-931-4968129
School of Chemical Engineering & Pharmaceutics, Henan University
of Science and Technology, Luoyang, 471003, China
w Electronic supplementary information (ESI) available: Experimental
details and characterization data for new compounds. See DOI:
0.1039/c2cc30429e
b
Current oxidative phosphonation of C(2)–H of 1a with 2a
turned out to be a quite low yield (o5%) in the presence of a
wide range of organic or inorganic oxidants except for K S O ,
1
2
2
8
This journal is c The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5181–5183 5181

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a
Table 1 Optimization of reaction conditions
Table 2 Pd-catalyzed direct phosphonation of azoles with dialkyl
a
phosphites
b
Yield (%)
Entry
Catalyst
Ligand
Oxidant
1
2
3
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
—
—
K
—
2
S
2
O
8
12
NR
56
56
27
47
47
56
10
38
26
55
48
54
34
23
41
55
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
K
K
K
K
K
K
K
K
K
K
K
K
K
K
K
K
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
O
8
O
8
O
8
O
8
O
8
O
8
O
8
O
8
O
8
O
8
O
8
O
8
O
8
O
8
O
8
O
8
c
4
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
5
6
7
8
9
PdCl
Pd(TFA)
PdCl (COD)
2
2
2
d
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
2
2
2
2
2
2
e
f
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
g
h
a
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), oxidant (1.5 mmol),
CN (3.0 mL) at 100 1C for 24 h under
air. HPLC yields. 50 mol% of L1. Argon atmosphere. Oxygen
L (30 mol%) and catalyst in CH
3
b
c
d
e
a
Isolated yields and all results were averaged by two runs.
f
g
h
atmosphere. 80 1C. 120 1C. 30 h.
that L2 or L3 instead of L1 is the better ligand choice.
Furthermore, it was found that the direct phosphonation of
benzoxazole was very sensitive to the oxygen, and even air
(Table S5, ESIw). With L2 as ligand and under an argon
atmosphere, phosphonation of benzoxazole reacted smoothly
to produce 3g in moderate yield, substitution with electron
donating groups on the phenyl ring gave rise to the yield
enhancement (3h–3j) and their Cl-substituted analogue also
afforded a similar yield of 3k. Similarly, replacement of
coupling partner 2a with 2b will increase the phosphonation
reactivity, giving moderate to good yield of the desired hetero-
cyclic phosphonate (3l–3p, 63–83%). Other aromatic sub-
strates such as N-methylbenzimidazole and N-methylindole
were also tested, unfortunately, they were inactive substrates
for this direct phosphonation.
which was identified as the most efficient of the re-oxidants
examined (Table S2, ESIw). Among the solvents tested,
CH CN gave the best result and reactions in other polar or
3
nonpolar solvents did not proceed to give a desirable amount
of the product (Table S3, ESIw). Accelerating efficiency of
some other amino acids and bidentate nitrogen ligands were
also investigated (entries 13–18 of Table 1 and Table S4,
ESIw), L3 and L7 gave a similar yield to that of L1, which
has been identified as the optimized ligand in the direct
phosphonation of benzothiazole derivatives with dialkyl
phosphites considering it is much cheaper and more easily
available.
With the promising results obtained in the model reaction,
we then examined the substrate scope of representative azoles
and dialkyl phosphites under the optimized reaction condi-
The mechanism for Pd-catalyzed phosphonation of aryl
halide with phosphite ester has been extensively studied by
2 2 2 8 3
tions (5 mol% Pd(OAc) /L1, K S O , CH CN, 100 1C). As
4b–d
17
and Stockland et al. To study the
shown in Table 2, a benzothiazole derivative bearing a methyl
group gave a lower yield of 3b (41%) in comparison with
non-substituted benzothiazole (56%). Introducing a chloride
substituent slightly enhanced the phosphonation reactivity,
affording 3c in 57% yield. Changing the phosphite coupling
partner to more steric demanding and electronic donating
diisopropyl phosphite (2b), benzothiazole itself and its deriva-
tives all reacted smoothly to afford the desired products
Stawinski et al.
mechanism of this novel C–P bond forming reaction, we
initially carried out a control phosphonation in the presence
of a radical scavenger (TEMPO), a similar yield of 3a was
obtained with that of the model reaction without TEMPO,
suggesting that current oxidative phosphonation may not be a
radical involving reaction. Measured pH value difference
between the start (E4.5) and the completion of reaction
+
(
3d–3f) in higher yields (45–70%) compared with the corres-
(E2.5) indicated that a number of H ions were generated
ponding phosphonation using 2a as a phosphite reagent.
Surprisingly, only 15% yield of 3g was obtained when the above
optimized conditions were extended to the oxidative phosphonation
of benzoxazole with 2a, re-optimization experiments indicated
from the cleavage of C–H and P(O)–H bonds. To gain more
information of the Pd-catalyst species involved in the catalytic
cycle, a representative phosphonation between 1a and 2b was
monitored by ESI/MS(+), which has been successfully employed
5
182 Chem. Commun., 2012, 48, 5181–5183
This journal is c The Royal Society of Chemistry 2012

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Scheme 2 Proposed mechanism for the direct phosphonation of azole.
5d,18
in studying many Pd-catalyzed reactions.
After stirring for
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II
Pd -catalyzed oxidation reactions have been typically recognized
II
0
8
9
to proceed via the Pd /Pd catalytic cycle in the presence of an
19
2
.
oxidant, such as benzoquinone, O , CuCl
2
However, all these
oxidants were inactive for current phosphonation, suggesting that
II
it may not proceed via Pd /Pd , but a Pd /Pd catalytic cycle.
0
II
IV
20
1
9,20
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a
possible catalytic cycle is drawn in Scheme 2. The reaction is
II
initiated by nucleophilic coordination of the phosphite to Pd
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II
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1
1
1
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IV
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In conclusion, we have discovered the first palladium-
catalyzed oxidative phosphonation of azoles with dialkyl
phosphites in high regioselectivity without additional base or
acid. Such transformation represents an atom-economical alter-
native to traditional phosphonation of Ar–X, which requires the
use of prefunctionalized arene and a stoichiometric amount of
base. The reactions afford a variety of 2-phosphonated azoles in
moderate to good yields and also may point a way to develop
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studies on the mechanism and synthetic application are in
progress.
(
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4
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1
Financial support from the Chinese Academy of Sciences and
the National Natural Science Foundation of China (21002106
and 21133011) is gratefully acknowledged.
3
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see: (b) O. Basle
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(
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IV
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This journal is c The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5181–5183 5183