Silver-catalyzed carbon - Phosphorus functionalization of N-(p-methoxyaryl)propiolamides coupled with dearomatization: Access to phosphorylated aza-decenones

Article abstract of DOI:10.1039/c4cc06923d

Silver-catalyzed cascade difunctionalization of N-(p-methoxyaryl)-propiolamides coupled with dearomatization was achieved and used to regiospecifically construct a variety of phosphorylated azadecenones bearing adjacent quaternary stereocenters under mild conditions in moderate to excellent yields.

Full text of DOI:10.1039/c4cc06923d

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Silver-catalyzed carbon–phosphorus functionalization
of N-(p-methoxyaryl)propiolamides coupled with
dearomatization: access to phosphorylated
aza-decenones†
Cite this: Chem. Commun., 2014,
50, 13998
Received 2nd September 2014,
Accepted 20th September 2014
Li-Jing Wang, An-Qi Wang, Yu Xia, Xin-Xing Wu, Xue-Yuan Liu and
Yong-Min Liang*
DOI: 10.1039/c4cc06923d
www.rsc.org/chemcomm
Silver-catalyzed cascade difunctionalization of N-(p-methoxyaryl)- utilized substrates for dearomatization en route to complex
propiolamides coupled with dearomatization was achieved and used natural products in total syntheses.9 In addition, several groups
to regiospecifically construct a variety of phosphorylated aza- have successively reported that silver salts could work with
decenones bearing adjacent quaternary stereocenters under mild Ph2(O)PH to form the active phosphinoyl radicals [Ph2P(O)ꢀ]
conditions in moderate to excellent yields.
which have been applied to the addition of unsaturated systems
in recent times.10 Inspired by these results, we decided to test
Organophosphorus compounds, belonging to a highly important whether silver can catalyze the addition of the P-radical to
class of compounds which have a wide range of applications in arylalkynes and direct cyclization with dearomatization to afford
organic synthesis,1 medicinal chemistry,2 and materials indus- the corresponding phosphonated spirocyclic compounds, which
tries,3 have drawn much attention from the synthetic community. are found in a wide variety of biologically active natural products
Recent studies have revealed that excellent bioactivities can be and pharmaceuticals. Herein, we describe a tandem preparation
reflected from heterocycles containing P-substituents,4 and the of phosphonated aza-decenones through silver-catalyzed carbon
continuing interest in the development of synthetic methods for phosphorus functionalization of N-( p-methoxyaryl)propiolamides
C–P bond construction was born in light of this.5 In recent years, coupled with dearomatization.
tremendous efforts have been made toward the C–P bond con-
At the outset of our studies, we chose N-(4-methoxyphenyl)-
struction and several extensively utilized methods have been N-methyl-3-phenylpropiolamide (1a) as the model substrate to
established and developed. Traditional methods for C–P bond optimize the reaction conditions (Table 1). Initially, the reaction
formation rely on the transition-metal catalyzed cross-coupling was carried out with diethyl H-phosphonate (2a) in the presence
reaction and the reaction of organometallic reagents with an of 1.0 equiv. of AgNO3 in CH3CN at 100 1C for 5 h. Gratifyingly,
electrophilic P-reagent.6 Most recently, the addition of P-centered the target product 3a was detected in 64% yield (Table 1, entry 1),
radicals to unsaturated systems which provides a direct and the structure of which was unambiguously confirmed by X-ray
atom economic approach for the synthesis of organophos- analysis.11 Encouraged by this result, we further optimized the
phorus compounds has once again been actively investigated. reaction conditions of this radical cascade process. Our focus
Whereas the addition of P-centered radicals to alkenes is was to decrease the loading of the silver catalyst; however, when
frequently used for the synthesis of organophosphorus com- the quantity of the catalyst was reduced to 10 mol%, only a trace
pounds, the related intermolecular addition to alkynes has been amount of 3a was observed (Table 1, entry 2). Interestingly,
less explored.7 Thus, the development of efficient P-radical upon introducing Mg(NO3)2Á6H2O as an additive, the yield
tandem procedures and alternative methods for C–P bond increased to 83% (Table 1, entries 3–4). Using Mg(NO3)2Á6H2O
construction is still desirable.
as an additive, we re-evaluated different silver catalysts but lower
Dearomatization reactions provide a powerful strategy for yields were obtained (Table 1, entries 5–7). Other nitrate addi-
the synthesis of useful hydrocarbons and alicyclic frameworks tives such as Cd(NO3)2Á4H2O, Ni(NO3)2Á6H2O, Co(NO3)2Á6H2O,
from readily available aromatic compounds.8 In particular, and NaNO3 were also investigated in this reaction but no better
phenols and related derivatives are by far the most frequently results were obtained (Table 1, entries 8–11). Decreasing the
reaction temperature led to yield reduction (Table 1, entry 12),
and the yield could not be improved upon increasing the loading
of diethyl H-phosphonate (2a) (Table 1, entry 13). Additionally, a
State Key Laboratory of Applied Organic Chemistry, Lanzhou University 730000,
P. R. China. E-mail: liangym@lzu.edu.cn
control experiment showed that, without the catalyst, Mg(NO3)2Á
† Electronic supplementary information (ESI) available. CCDC 1022183. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc06923d 6H2O alone could not promote this reaction (Table 1, entry 14).
13998 | Chem. Commun., 2014, 50, 13998--14001
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Table 1 Optimization of reaction conditionsa
Entry
Cat. (mol%)
Additive (equiv.)
Yieldb (%)
1
2
3
4
5
6
7
8
AgNO3 (100)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
Ag2O (10)
AgOTf (10)
Ag2CO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
—
—
—
64
Trace
65
83
76
82
79
74
77
80
63
61
69
nr
Mg(NO3)2Á6H2O (1.0)
Mg(NO3)2Á6H2O (0.5)
Mg(NO3)2Á6H2O (0.5)
Mg(NO3)2Á6H2O (0.5)
Mg(NO3)2Á6H2O (0.5)
Cd(NO3)2Á4H2O (0.5)
Ni(NO3)2Á6H2O (0.5)
Co(NO3)2Á6H2O (0.5)
NaNO3 + H2O (0.5)
Mg(NO3)2Á6H2O (0.5)
Mg(NO3)2Á6H2O (0.5)
Mg(NO3)2Á6H2O (0.5)
9
10
11
12c
13d
14
a
Reaction conditions: 1a (0.2 mmol), 2a (2.0 equiv.), AgNO3 (0.02 mmol),
Mg(NO3)2Á6H2O (0.1 mmol), CH3CN (1 mL), 100 1C (oil bath) for 5 h.
b
c
d
Isolated yield. The reaction was run at 80 1C. The reaction was
run under 0.6 mmol of 2a with 1a (0.2 mmol) and Mg(NO3)2Á6H2O
(0.1 mmol).
After a series of detailed investigations, the reaction conditions
were eventually optimized as shown in Table 1, entry 4: 1.0 equiv.
of 1a and 2.0 equiv. of 2a with 0.5 equiv. of Mg(NO3)2Á6H2O and
10 mol% of AgNO3 in the presence of 1 mL of CH3CN at 100 1C.
With the optimized reaction conditions in hand, the radical
phosphonation-ipso-cyclization method was applied for various
substrates (Scheme 1). The reaction could proceed well by using
diverse dialkyl H-phosphonates to afford the desired products in
good yields (3a–c). Diphenylphosphine oxide is also a suitable
P-radical precursor for this ipso-cyclization, and the corresponding
product 3d was isolated in 71% yield. Subsequently, the substitu-
ents, either aryl or alkyl, at the terminal CRC bond were subjected
to the optimized reaction conditions. We found that substrates 1e–l
bearing an electron-donating or an electron-withdrawing aromatic
R3 group were tolerated well. However, compounds 1m–n with an
alkyl R3 group only gave the desired phosphorylated aza-decenones
in yields of 38% and 41%, respectively. To our delight, the reaction
worked well with compound 1o with a cyclopropyl group at R3,
which proceeded to give the desired product 3o in a yield of 67%.
Furthermore, we focused on the N-substituent (R2). Substrates with
ethyl and benzyl substituents, both afforded the corresponding
phosphorylated aza-decenones in good yields (3p–q). While sub-
Scheme 1 Silver-catalyzed phosphorus ipso-carbocyclization of 4-(p-
methoxyarylalkynes).
strate 1r, having an N-acetyl group, gave the desired product in a the addition of 1.0 equivalent of TEMPO suppressed the carbon
yield of only 47%, and the reaction of 1s bearing a free N–H group phosphorylation process, thus suggesting that this transformation
was unsuccessful. We further tested the effect of substituents at R1. might involve a radical process (Scheme 2a). When 1a was
Substrate 1t underwent ipso-cyclization smoothly to give the corre- investigated under the standard conditions without 2a, the
sponding product in excellent yield, while compound 1u gave the ipso-cyclization product 4a was not detected (Scheme 2b). More-
desired product in a yield of only 16%. We concluded that the over, considering a pioneering report that AgNO3 can react with
failure to obtain a good yield of 3u may be the result of the steric Ph2(O)PH to form the complex of Ph2(O)PAg,10 1.0 equivalent of
effect of the substituent at R1.
the [Ph2(O)PAg] complex was used under the standard conditions
In order to gain insight into the mechanism of this reaction, without 2a; however the supposed product 3d was not detected
some preliminary studies were carried out (Scheme 2). As follows, either with or without AgNO3 (Scheme 2c). Hence, we conclude
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Scheme 3 Possible mechanism.
We thank the National Science Foundation (NSF-21072080)
and the National Basic Research Program of China (973 Program)
2010CB8-33203 for financial support. We also acknowledge sup-
port from the ‘‘111’’ Project and Program for Changjiang Scholars
and innovative Research Team in University (IRT1138).
Scheme 2 Control experiments.
that (1) the first step is the phosphonation with AgNO3.
(2) Ph2(O)PAg could not add to 1a to form the silver species
and P-radicals are active intermediates in this process.10f
However, Ph2(O)PAg (10 mol%) could catalyze the phosphorus
ipso-carbocyclization of 1a under the optimized reaction con-
ditions to give 3a in 74% yield, thus suggesting that P-radicals
are generated from dialkyl H-phosphonates oxidized by AgNO3
or [Ph2(O)PAg] (Scheme 2d).
A plausible mechanism can be proposed based on the
previous reports and above findings (Scheme 3).8a,10a, f Firstly,
a phosphorus radical B is generated from diethyl H-phosphonate
2a by AgNO3 or the intermediate A. After the selective addition
of the P-radical to the a-position of the CQO bond in 1a, the
resulting vinyl radical C which is stabilized by the phenyl group,
undergoes thermodynamically controlled 5-exo cyclization onto
the aromatic ring with p-MeO to give spiro intermediate D.
Subsequently, the spiro intermediate D is oxidized by Ag(I)
to oxonium ion E along with HNO3 and Ag(0). Then, oxonium
ion E is transformed into 3a and in the presence of HNO3,
Ag(0) is oxidized to Ag(I) which will participate in the next
reaction cycle.
In summary, we have developed a highly efficient protocol
for the preparation of various phosphorylated aza-decenones
by silver-catalyzed cascade difunctionalization of alkynes
involving phosphonation of N-( p-methoxyaryl)propiolamides,
5-exo cyclization, and dearomatization. The cheap and nontoxic
silver salt was employed to catalyze the carbon phosphonation
of arylalkyne alkynoate coupled with dearomatization for
the first time. Because of its wide substrate scope and opera-
tional simplicity, this reaction should be useful for medicinal
chemistry and other applications. Work to probe the detailed
mechanism and apply the reaction in organic synthesis is
currently underway.
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