Silver-catalyzed synthesis of 3-phosphorated coumarins via radical cyclization of alkynoates and dialkyl H -phosphonates

Article abstract of DOI:10.1021/ol5013839

Ag₂CO₃-catalyzed difunctionalization of alkynes via a radical phosphonation and C-H functionalization tandem process was developed to synthesize various 3-phosphonated coumarins in moderate to high yields with high regioselectivity. A catalytic amount of cheap and nontoxic silver salt was employed in the domino C-P and C-C formation of alkynoates for the first time. Mechanistic studies indicate that the reaction pathway might proceed via the generation and cyclization of a phosphonated vinyl radical intermediate.

Full text of DOI:10.1021/ol5013839

Letter
pubs.acs.org/OrgLett
Silver-Catalyzed Synthesis of 3‑Phosphorated Coumarins via Radical
Cyclization of Alkynoates and Dialkyl H‑Phosphonates
Xia Mi,† Chenyang Wang,† Mengmeng Huang,*,† Jianye Zhang,† Yusheng Wu,*,†,‡ and Yangjie Wu*,†
†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, P. R. China
‡Tetranov Biopharm, LLC., 75 Daxue Road, Zhengzhou 450052, P. R. China
S
* Supporting Information
ABSTRACT: Ag2CO3-catalyzed difunctionalization of alkynes via
a radical phosphonation and C−H functionalization tandem
process was developed to synthesize various 3-phosphonated
coumarins in moderate to high yields with high regioselectivity. A
catalytic amount of cheap and nontoxic silver salt was employed in
the domino C−P and C−C formation of alkynoates for the first
time. Mechanistic studies indicate that the reaction pathway might
proceed via the generation and cyclization of a phosphonated vinyl
radical intermediate.
romatic organophosphorus compounds could be found in
the corresponding phosphonated coumarins as potential
Amany natural products, pharmaceuticals, materials science, pharmaceutical agents12 (Scheme 1). Herein, we describe a
and synthetic intermediates.1 In light of their importance, the
development of C−P bond construction has been a research
focus up to now. Several extensively utilized methods of C−P
bond construction have been established and developed, for
example, the traditional reaction of an electrophilic phosphorus
reagent with a carbon nucleophile2 and transition-metal-
catalyzed cross-coupling reactions.3 After approximately two
decades of relative neglect, the addition of P-centered radicals
to unsaturated systems is once again being actively investigated
and has become a reliable procedure for the synthesis of
organophosphorus compounds.4 Recently, the intermolecular
addition of P-centered radicals to alkynes has attracted great
attention.4a Generally, the synthetic value of radical additions to
alkynes is due to the highly reactive vinyl radicals formed by
this step which can be trapped by fast cyclization or addition
onto other π-systems. To the best of our knowledge, only very
few cascade reactions initiated by the addition of P-centered
radicals to alkynes have been reported.5 Thus, the development
of efficient P-radical tandem procedures is highly in demand
and a promising alternative for the construction of highly
complex organophosphorus frameworks.
Generally, P-centered radicals are generated from radical
initiators such as peroxides,6 azo compounds,7 R3B/O2,8 Ag/
K2S2O8,9 etc. Since the seminal contribution by Ishii,
manganese salts have been generally used in the phosphorus
radical chemical field.5d,e,10 Very recently, several groups have
successively reported that silver salts could work with
Ph2(O)PH to form the active phosphinoyl radicals [Ph2P(O)•]
which have been applied to the addition of unsaturated
systems.11 With our interest in phosphonated coumarins,3j we
hypothesize that the silver might catalyze the addition of P-
radical to alkynoates and conduct the direct cyclization to afford
Scheme 1. Silver-Catalyzed Tandem Coupling Reaction
domino preparation of 3-phosphonated coumarins through a
silver-catalyzed sequential radical C−P/C−C process between
aryl alkynoates and dialkyl H-phosphonates.
At the onset of our studies, the tandem radical phosphona-
tion−cyclization of readily prepared phenyl alkynoate (1a) with
diethyl H-phosphonate (2a) was investigated in the presence of
1 equiv of AgNO3 in CH3CN at 100 °C for 12 h. To our
delight, the target product 3a was detected in 23% yield (Table
1, entry 1). The structure of 3a was unambiguously confirmed
by X-ray analysis (Figure 1). Motivated by this result, we
further optimized the reaction conditions of this radical cascade
process. When the loading of AgNO3 was reduced to 10 mol %,
only a trace amount of 3a was observed (Table 1, entry 2).
Interestingly, introducing Mg(NO3)2 as an additive, the yield
increased to 47% and was improved further to 67% with the
addition of 4 Å MS (Table 1, entries 3−5). Using Mg(NO3)2
and 4 Å MS as additives, the different silver and copper salts
were evaluated. The results revealed that Ag2CO3 gave the
highest yield (Table 1, entries 6−12). Other nitrate additives
such as Cd(NO3)2·4H2O, Ni(NO3)2·6H2O, Co(NO3)2·6H2O,
and NaNO3 also performed in this reaction (Table 1, entries
13−16). Decreasing the reaction temperature led to the yield
Received: May 14, 2014
© XXXX American Chemical Society
A
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a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Silver-Catalyzed Phosphorus Carbocyclization of
Alkynoates
a
,b
b
entry
cat. (mol %)
additive (equiv)
yield (%)
c
1
AgNO3 (100)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3(10)
AgOAc (10)
Ag2O (10)
−
−
23
trace
47
67
53
55
56
57
50
80
trace
39
45
50
40
40
71
79
nr
c
2
c
3
Mg(NO3)2 (0.3)
Mg(NO3)2 (0.3)
Mg(NO3)2 (0.5)
Mg(NO3)2 (0.3)
Mg(NO3)2 (0.3)
Mg(NO3)2 (0.3)
Mg(NO3)2 (0.3)
Mg(NO3)2 (0.3)
Mg(NO3)2 (0.3)
Mg(NO3)2 (0.3)
Cd(NO3)2 (0.3)
4
5
6
7
8
AgOTf (10)
AgBF4 (10)
Ag2CO3 (10)
CuCl (10)
9
10
11
12
13
14
15
16
Cu(OAc)2(10)
Ag2CO3 (10)
Ag2CO3 (10)
Ag2CO3 (10)
Ag2CO3 (10)
Ag2CO3 (10)
Ag2CO3 (10)
−
Ni(NO3) (0.3)
2
Co(NO3)2 (0.3)
NaNO3 (0.3)
d
17
Mg(NO3)2 (0.3)
Mg(NO3)2 (0.3)
Mg(NO3)2 (0.3)
e
18
19
a
Reaction condition: 1a (0.25 mmol), 2a (3 equiv), catalyst, additive,
4 Å MS (50 mg), CH3CN (1 mL), 100 °C (oil bath) for 12 h.
b
c
d
e
Isolated yield. Without 4 Å MS. 90 °C (oil bath). 18 h.
a
Reaction condition: 1 (0.25 mmol), 2 (3 equiv), Ag2CO3 (10 mol %),
Mg(NO3)2 (0.3 equiv), 4 Å MS (50 mg), solvent (1 mL), 100 °C (oil
bath) under air for 12 h. b Isolated yields. c A total yield of two isomers
is shown.
ing coumarins in moderate to good yields (3e−l). With a
strong electron-withdrawing substituent (CF3) on the phenoxy
ring, the corresponding product 3m was only obtained in 47%
yield. The steric hindrance was very distinct. With a methyl
group on the ortho-position of the phenoxy ring, no desired
product 3n was observed under optimal reaction conditions. To
investigate the regioselectivity of the discovered cascade
reaction, aryl alkynoates bearing a meta-substituted phenoxy
ring (2o−q) were prepared and successfully converted into the
corresponding products in good yields. Whereas 3o, 3o′ and
3p, 3p′ were formed in a ratio of two isomers (1.2:1 and 1.5:1
respectively), product 3q was obtained in high yield with
complete regiocontrol. These results indicated that cyclization
preferably occurred at the position distal to the meta
substituent. On the other hand, we also evaluated functional
groups linked with the alkynyl. Different substituted aryl groups
underwent the reaction smoothly and converted into the
corresponding products with good yields regardless of electron-
donating or -withdrawing groups (3r−w). In particular, phenyl
Figure 1. X-ray structure of compound 3a.
reduction (Table 1, entry 17), and the yield could not be
increased further with a longer reaction time (Table 1, entry
18). In addition, a control experiment showed that, without the
catalyst, Mg(NO3)2 alone could not promote this reaction
(Table 1, entry 19).
With optimized reaction conditions in hand, the radical
phosphonation−cyclization method was applied for various
substrates (Scheme 2). The reaction could proceed well by
using diverse dialkyl H-phosphonates to afford the correspond-
ing products in good yields (3a−c). Expectedly, diphenylphos-
phine oxide is also a suitable P-radical precursor for this
transformation, and the desired product 3d was isolated in 80%
yield. Subsequently, various alkynoates were subjected to the
optimized reaction conditions (3e−w). A variety of aryl 3-
phenylpropiolates with para and meta substituents on the
phenoxy ring were smoothly cyclized to obtain the correspond-
B
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2-octynoate was also found to be suitable for the reaction with a
moderate yield (3w).
Scheme 5. Possible Mechanism
To gain insight into the mechanism of this transformation, a
series of control experiments were carried out (Scheme 3). The
Scheme 3. Control Experiments
gives the vinyl radical C stabilized by the phenyl group. The
resulting vinyl radical C undergoes cyclization to generate the
intermediate D. Subsequently, a single-electron transfer (SET)
from D to silver(I) would release the product 2a along with
HNO3 and silver(0). In the presence of HNO3, the silver(0)
was oxidized to silver(I).
In summary, we have demonstrated a novel approach to the
synthesis of 3-phosphonated coumarins starting with readily
prepared alkynoates and the commercially available H-
phosphonates as a P-radical precursor. Various 3-phosphonated
coumarins were prepared with high regioselectivity in moderate
to high yields. The cheap and nontoxic silver salt was employed
in catalyzing the carbon phosphonation of alkynoate for the
first time. A plausible mechanism was proposed involving
phosphonation via the addition of P-radicals, and radical
cyclization. Further mechanistic studies and extension of the
current method to other substrates are underway.
reaction was completely suppressed in the presence of 1.0 equiv
of TEMPO as a radical scavenger (Scheme 3a). It was
consistent with our hypothesis that the reaction proceeds via a
radical pathway. When 1a was performed under the standard
conditions without 2a, C−H functionalization did not occur,
and the cyclization product 4a was not detected (Scheme 3b).
Thus, we conclude that the first step is the phosphonation with
Ag2CO3.11c When the [Ph2P(O)Ag] complex was used in a
stoichiometric fashion, no conversion of 1a was observed with
or without Ag2CO3. In contrast to previously reported
examples,11b,c our results indicated that (1) Ph2(O)PAg could
not add to 1a to form the silver species and (2) P-radicals are
active intermediates in this process.11e However, in the
presence of a catalytic amount of [Ph2P(O)Ag], the reaction
of 1a and 2a could proceed smoothly to give 3a in 70% yield,
thus suggesting that P-radicals are generated from dialkyl H-
phosphonates oxidized by Ag2CO3 or [R2P(O)Ag] (Scheme 3c,
d). To further understand the catalytic cycle of the carbon
phosphorylation, the intra- and intermolecular kinetic isotope
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectroscopic data and copies of
NMR spectra for all new compounds and X-ray crystallographic
data for compound 3a. This material is available free of charge
via the Internet at http://pubs.acs.org.
effects (KIE) were investigated (the intramolecular KH/KD
=
1.27 and intermolecular KH/KD = 1.07) (Scheme 4), which
indicate that C−H bond cleavage on the phenoxy ring is not
involved in the rate-determining step.
AUTHOR INFORMATION
Corresponding Authors
■
With these results in hand, a plausible mechanism involving a
radical-type catalytic cycle is depicted in Scheme 5. First, a
phosphorus radical B is generated from diethyl H-phosphonate
*E-mail: hmm@zzu.edu.cn.
*E-mail: yusheng.wu@tetranovglobal.com.
*E-mail: wyj@zzu.edu.cn.
11e
2a by Ag2CO3 or the intermediate A. Selectivity addition of
the P-radical to the α-position of the CO bond in 1a then
Notes
Scheme 4. Deuterium Labelling Experiments
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science
Foundation (NSF) of China (Nos. 21172200 and 21302172).
■
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