Aerobic oxidative alkynylation of H-phosphonates and amides: An efficient route for the synthesis of alkynylphosphonates and ynamides using a recyclable Cu-MnO catalyst

Article abstract of DOI:10.1039/c9cy00275h

An atom-economical and efficient route for the synthesis of alkynylphosphonates and ynamides by aerobic oxidative alkynylation of H-phosphonates and amides with both aliphatic and aromatic alkynes using our synthesized recyclable heterogeneous Cu-MnO catalyst has been developed. The phosphorylation was carried out under base- and ligand-free conditions, and in the presence of air as the sole oxidant. The reaction is compatible with a wide variety of functional groups and generates alkynylphosphonate and ynamide products in good to excellent yields. Both reactions can be scaled up to the gram scale without any decrease in the reaction yield and the reaction time is less compared to literature reports. The catalyst is recyclable and reused several times without any significant loss of reactivity.

Full text of DOI:10.1039/c9cy00275h

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DOI: 10.1039/C9CY00275H
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Aerobic Oxidative Alkynylation of H-Phosphonates and Amides:
An Efficient Route for the Synthesis of Alkynylphosphonates and
Ynamides by Recyclable Cu-MnO Catalyst
Received 00th January 20xx,
Accepted 00th January 20xx
Harshvardhan Singh, Tapan Sahoo, Chiranjit Sen, Sunil M. Galani and Subhash Chandra Ghosh*
DOI: 10.1039/x0xx00000x
www.rsc.org/
ABSTRACT: An atom-economical and efficient route for the synthesis alkynylphosphonates and ynamides by aerobic oxidative alkynylation
of H-phosphonates and amides with both aliphatic and aromatic alkynes using our synthesized recyclable heterogeneous Cu-MnO catalyst
has been developed. The phosphorylation was carried out under base and ligand-free conditions, and in the presence of air as the sole
oxidant. The reaction is compatible with a wide variety of functional groups and generates alkynylphosphonates and ynamides products in
good to excellent yields. Both the reactions can be scaled up to gram scale without any decrease in the reaction yield and reaction time is
less compared to the literature report. The catalyst is recyclable and reused for several times without any significant loss of the reactivity.
Introduction
explored. In 2009, Zhao and Han et al. first reported this strategy
[25-26]
using CuI as a catalyst, Et3N as a base in DMSO solvent.
Zhao
Direct functionalization of the C(sp)-H bond of the terminal alkyne
for the construction of C (sp)-P bond and C (sp)-N bond is highly
demanding due to their great interest in chemistry and biology.[1-15]
The importance of phosphorous compounds in organic synthesis and
their presence in bioactive molecules motivated chemists for the
and Chen et al. reported a similar reaction using CuSO4. 5H2O as a
[27]
catalyst and Et3N as a base.
Base is required for their system to
deprotonate the terminal alkyne to prepare intermediate copper
acetylide species. Base free approaches were reported by Wang et
al. using silica-supported carbene-Cu(II) catalyst, [28] but the catalyst
preparation is not so straightforward and by Moglie et al. using
homogeneous Cu2O as a catalyst.[29] Other than copper, expensive
palladium catalyzed, silver mediated dehydrogenative coupling of
terminal alkynes with secondary phosphine oxides was reported by
Han et al.[30] and Lei et al. [31] More recently, Han et al. reported the
same in the absence of silver with only palladium catalyst. [32] Despite
the advancement of C(sp)-H bond preparation, the majority of the
reactions were carried out under the homogeneous condition, with
limitations like the use of an expensive catalyst, recyclability, and
chances of metal contamination in the final product which is mostly
undesired in the synthesis of pharmaceutical molecules. Hence, the
development of an atom-economical, environmentally benign and
sustainable heterogeneous catalyst for C(sp)-P bond preparation is
still demanding for the advancement in this area. As part of our
ongoing research on heterogeneous catalysis, we have reported
lotus shaped Cu-MnO catalyzed direct C(sp2)-H halogenation, and
amination reaction, [33-35] we have drawn our attention in the field of
C(sp)-P bond and C (sp)-N bond construction. Herein, we wish to
report an efficient catalytic system for oxidative coupling reaction of
development of new methodologies for C(sp)-P bond forming
[8-15].
reactions.
Alkynylphosphonates, containing a reactive triple
bonds and a phosphoryl groups, are a very important class of
functional molecule. Therefore, a considerable effort has been made
for the synthesis of alkynylphosphonates. Traditionally, reaction of
(RO)2P(O)Cl as phosphorous electrophile with Li or Mg acetylides is
one of the most common and effective method used for the
[16-17]
synthesis of alkynylphosphonates.
However, it has several
limitation like a) use of hazardous chemicals and generates toxic
waste; and b) poor functional group tolerance. Other alternative
strategies for the synthesis of alkynylphosphonates are the reaction
[18-19]
of 1,1-dibromo-1-alkenes with H-phosphites,
oxidative
decarboxylative coupling of aryl propiolic acids with dialkyl H-
phosphonates, [20-21] cross-coupling with alkynylcopper reagents and
1-alkynyl sulfones [22] and others [23-24]. On the other hand, the atom
economical strategy, coupling of terminal alkynes with H-
phosphonates to synthesize alkynylphosphonates was not fully
Natural Products and Green Chemistry Division
Academy of Scientific and Innovative Research,
CSIR-Central Salt and Marine Chemicals Research Institute, G.B. Marg, Bhavnagar-
364002, Gujarat, India.
E-mail: scghosh@csmcri.res.in; schandra1976@gmail.com
Electronic Supplementary Information (ESI) available: experimental details, copy of
1H and 13C and 31 P NMR spectra See DOI: 10.1039/x0xx00000x
terminal
alkynes
with
H-phosphonates
to
synthesize
alkynylphosphonates using our recently developed reusable
spherical Cu-MnO catalyst; the same catalyst also works for the
synthesis of ynamides from amide and alkyne coupling.
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Table 1: Optimization of alkynylation of dialkyl phosphites [a]
Result and discussions
Catalyst preparation
View Article Online
DOI: 10.1039/C9CY00275H
O
P
H
O
Catalyst, Air,
H
O
+
H2O
Br
P
O
+
O
O
Solvent, temp., time
Br
The spherical -MnO2 was prepared by our reported procedure,[36]
first the MnCO3 was synthesized by hydrothermal conditions, using
Mn(OAc)2,4H2O, ammonium carbonate, and oxalic acid as a chelating
agent. After that, the material was calcined at 350C in aerobic
conditions to get spherical shape -MnO2. Later, copper
[Cu(OAc)2.H2O] impregnation was carried out by evaporating to
dryness methodology [33] followed by calcination at 350 C under 10%
H2 in N2 flow, for 6h. The synthesized Cu-MnO catalyst was fully
characterized by SEM, TEM, XRD, and XPS, during calcination, under
a hydrogen atmosphere, the manganese (IV) oxide reduces to
manganese (II) oxide. From SEM and TEM images (Figure 1, a-d)
revealed that the Cu-MnO catalyst is spherical in nature with a
diameter of 3-4 µm. In the XRD pattern of 5 %, Cu-MnO, a tiny peak
of metallic Cu was observed (figure 1 e), which indicates that upon
calcination under reducing environment Cu(II) reduces to Cu(0)
species and homogeneously distributed over the MnO moiety as
confirmed by elemental mapping in EDS-SEM analysis (see ESI for
details) . XPS spectra confirmed the presence of both Cu (0) and Cu
(II) species in the surface of the catalyst. [33]
2a
3a
1a
Entry
Catalyst
Solvent
Toluene
THF
CH3CN
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
T (C)
100
100
100
100
100
50
Yield (%)
32
1
2
3
4
5
6
7
8
5 wt% Cu-MnO
5 wt% Cu-MnO
5 wt% Cu-MnO
5 wt% Cu-MnO
5 wt% Cu-MnO
5 wt% Cu-MnO
5 wt% Cu-MnO
5 wt% Cu-MnO
MnO
Trace
Trace
38
94
56
trace
58[b]
NR
NR
NR
NR[c]
94[d]
rt
100
100
100
100
100
100
9
10
11
12
13
γ-MnO2
-
5 wt% Cu-MnO
5 wt% Cu-MnO
a) Standard reaction conditions: 0.25 mmol, H-phosphonates 2 equiv, solvent 1 ml,
catalyst 12 mg (3.75 mol% Cu), temp: as mentioned in the table, in Air, for 1.5h; b)
diethyl phosphite 1 equiv.; c) reaction in N2 atmosphere; d) oxygen atmosphere
with 4-bromophenylacetylene (1a), and diethyl phosphite (2a) was
selected as a model substrate to optimize the reaction condition
(Table 1). Our initial investigation started using our developed
catalyst 5 wt% Cu on MnO, 1a reacted with 2a (2 equiv.), in toluene
solvent at 100°C in a closed carousel reaction tube with Air, for 1.5 h
40% consumption of 1a was observed and produced desired coupled
product diethyl ((4- Bromophenyl)ethynyl)phosphonate, 3a in 32%
isolated yield (Table 1, entry 1). Encouraged by the result, we first
screen the solvents for this coupling reaction, as reported[29] solvents
also play a crucial role in this reaction. However, THF, acetonitrile
does not work well (entry 2 and 3), whereas DMF showed similar
reactivity, 38% of the desired product was obtained (entry 4). To our
delight, when DMSO was used solvent reaction goes smoothly, and
excellent yield of 3a (94%, entry 5) was observed. We have tried to
reduce the reaction temperature at 50C only 56% and at room
temperature trace amount of product was obtained. When we
reduce the loading of phosphite to 1 equiv, (1: 1 ratio), we observed
58% of the 3a. Then, we check the reaction without Cu, in both MnO
and MnO2 under similar reaction condition no reaction takes place,
so copper is essential for the reaction. As expected, in the absence of
catalyst no reaction was observed (entry 11). After that we have
carried out the reaction under the inert condition to check the role
of oxygen, no reaction took place, so oxygen is also essential for the
reaction. Instead of air when we carried out the reaction under
oxygen, similar reactivity was observed (entry 13).
Figure 1: (a) and (b) SEM images, (c) and (d) TEM images of the synthesized Cu-
MnO catalyst, (e) XRD pattern of synthesized Cu-MnO and MnO catalyst; (f) Cu 2p
XPS spectra of the 5% Cu-MnO catalyst
With the optimization condition in hand (Table 1, entry 5), we next
examined the scope and limitation of the substituted
phenylacetylene. As shown in Table 2, various functional group
including electron donating group and electron withdrawing group
at the para position of the phenyl ring works well and provided
alkynylphosphonates products in good to excellent yields.
Reaction Optimization
After synthesis and complete characterization of the Cu-MnO
catalyst, we have started our investigation, for C-P bond formation
2 | J. Name., 2012, 00, 1-3
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Table 2: Substrate scope of alkynylation of H-phosphonatesa
phosphonate like dimethyl phosphite and dibutyl phVoisewphAirttieclse Ownelirnee
also tested with a coupling reaction with pDhOenI:y1l0a.c1e0t3y9l/eCn9eC,Ya0n0d27w5He
got excellent yield (3t, 90% and 4t, 92%) of the corresponding
alkynylphosphonates products. One interesting thing we have
observed that when free lone pair is available in the aryl substituents,
like presence of OMe, NMe2 or CN functional group (3f,g,h, k, m and
4f,g,h, k, m) on aromatic ring, little lower yield was observed, might
be they act as a ligands (Lewis base donors) and coordinates with the
copper.
R2
O
R2
O
H
H
O
P
Cu-MnO, air
P
R2
R1
H2O
O
+
R1
O
DMSO, 100C, 1.5 h
R2
O
R
O
R
O
P
3a
O
P
, 94%, R = Br
O
P
O
O
R
3b, 93%, R=
H
O
O
O
3c
3d
3e
, 94%, R = F
,
97%, R = Me
,95%, R = tBu
R
3l
,
94%, R = -Et
3f
, 78%, R = OMe
3i
3j
, 87%, R = CF3
94%, R = Cl
4l, 91%, R = -iPr
On the other hand, Ynamides are also essential synthetic
3g
, 83%, R = NMe2
,
3h,
3k,
88%, R = CN
81%, R = OMe
intermediate in organic synthesis, and they are also a useful
[37-48]
substrate in several organic transformations.
Cu-catalyzed
R
O
O
O
R
O
P
4a
4b
4c
4d
4e
, 93%, R = Br
R
P
oxidative direct amidation of a terminal alkyne with amide for the
synthesis of ynamides are first reported by Stahl and co-workers
O
P
, 92%, R=
H
O
O
O
, 90%, R = F
O
, 95%, R = Me
, 94%, R = tBu
, 81%, R = OMe
[49]
using 5 equivalent amides, 20 mol% catalyst loading and ligand.
O
R
4i
4j
4k,
, 86%, R = CF3
92%, R = Cl
4f
4g
Cu(OH)2 catalyzed cross-coupling of a terminal alkyne with amides (3
equivalent) reported by Mizuno and co-workers. [50-51] Where they
have mentioned that highly dispersed Cu(OH)2 supported on Al2O3
and TiO2 as a catalyst were not effective for cross coupling. Several
3m
, 62%, R = -Et
4m, 63%, R = -iPr
,
, 79%, R = NMe2
4h,
79%, R = OMe
72%, R = CN
R
O
R
O
O
R
O
P
R
O
P
R
O
groups also reported the Cu catalyzed oxidative amidation of a
O
O
O
O
[52-53]
P
terminal alkyne with N-nucleophile.
We believe that our
R
O
N
, 38% R = -Et
developed heterogeneous Cu-MnO catalyst could be a suitable
catalyst for cross-coupling reaction of a terminal alkyne with amide.
We have begun to investigate the reaction with phenylacetylene and
oxazolidin-2-one (2 equiv) in the presence of our developed 5 wt%
Cu-MnO catalyst under an oxygen atmosphere in toluene at 100 C,
but unfortunately the desired ynamide was not obtained. We
realized that a Brønsted base might be required for this reaction,
which could help to abstract the proton from the alkyne to generate
reactive copper acetylides and also abstract proton from amide
derivatives to make it more reactive, so we have planned to use
Na2CO3 and NaHCO3 as a base. To our delight, in the presence of a
suitable base, the reaction proceeds excellently, and almost
quantitative yield of ynamide was obtained (97-98%, entries 2-
3p
4p
4q
, 91% R = -Et
, 92%, R = -iPr
, 88%, R = -Butyl
3o
, 89% R = -Et
4o,
3n
4n, 37%, R = -iPr
90%, R = -iPr
R
R
R
O
R
O
P
R
O
O
R
O
P
O
P
O
O
O
3
7
3r
, 95% R = -Et
4r,
3s
3t,
90% R = -Me
, 94% R = -Et
4s,
94%, R = -iPr
4t
91%, R = -iPr
, 92%, R = -Butyl
a Standard reaction conditions: 0.25 mmol, H-Phosphonates 2 equiv, DMSO 1 ml,
5% Cu-MnO catalyst 12 mg (3.75 mol% Cu), 100 C, in Air, for 1.5h
Simple phenyl acetylene went very well, and excellent yield was
observed (93%, entry 3b), other moderate to weak electron
withdrawing group and electron donating group like bromo, fluoro,
methyl, tert-butyl showed high reactivity and furnished the desired
product in excellent yields (entries 3a-3e).The derivatives with strong
electron donating group such as methoxy (78%, 3f), and
dimethylamine (83%, 3g) produced the desired products in good
yields. Whereas strong electron withdrawing group nitrile works
well, excellent yield (88%, 3h) of the desired product was observed.
Keeping the functional group, e.g., trifluoromethyl, chloro, methoxy,
and methyl at ortho and meta position of the phenyl ring, similar
reactivity was observed (81-94%, entries 3i-3l). Other aromatic and
heteroaromatic alkynes were also tested and found to be a good
substrate, phosphorylation takes place with moderate to good
yields. Low yield of pyridine derivative (3n, 38%) was achieved, may
be due to the coordination of copper with pyridine. Aliphatic
terminal alkynes were also successfully phosphorylated under our
advanced catalytic system and gave excellent yields of desired
alkynylphosphonates products (3o-3s, 89-95%). Next, we examined
diisopropyl phosphite as phosphorylating agent for all the substrates,
to our delight phosphorylation proceeds smoothly and furnished the
corresponding alkynylphosphonates in good to excellent yield (up to
95%, entries 4a-4s) for both aromatic and aliphatic alkynes. Besides
diethyl phosphite and diisopropyl phosphite other alkyl H-
Table 3: Optimization for ynamide synthesisa
O
O
H
O
N
Conditions
HN
O
+
Entry
Catalyst
Solvent
Base
T (C)
100
Yield (%)
1
2
3
4
5 wt% Cu-MnO
5 wt% Cu-MnO
5 wt% Cu-MnO
5 wt% Cu-MnO
toluene
toluene
toluene
toluene
-
0
Na2CO3
NaHCO3
Na2CO3
100
100
100
98
97
75b
5
6
5 wt% Cu-MnO
5 wt% Cu-MnO
toluene
toluene
Na2CO3
Na2CO3
100
100
Tracec
58d
a) Standard reaction conditions: 0.25 mmol phenylacetylene, 2-Oxazolidone (2
equiv., 0.5 mmol), solvent 1 ml, catalyst 12 mg (3.75 mol% Cu), base (2 equiv.),
100C, under O2 atm., for 2h; b) reaction in air atm.; c) reaction in N2 atmosphere;
d) 2-oxazolidone 1.2 equiv.
3, table 3). Further screening of solvents revealed that toluene was
the best solvent (ESI, table S1). We have run the reaction in the
presence of air instead of pure oxygen, and slightly lower yield (75%,
entry 4) was observed. On the contrary, in the inert atmosphere, no
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ynamides product was obtained, which indicates that molecular up to 1 gram scale, alkynylphosphonates (3b) waVsiewsuAcrtcicelessOfnulilnlye
DOI: 10.1039/C9CY00275H
oxygen as an oxidant is essential for this reaction. Further decreasing prepared with similar yields (93%).
the amount of nucleophile, leads to lower in ynamides yield and
The hot filtration test confirmed the heterogeneity of the reaction.
We monitored the reaction progress after taking out the reaction
mixture via cannula to remove the catalyst. No, the further reaction
was observed, which suggests that the active catalyst was not
leached out to the solution and the reaction is heterogeneous in
nature. ICP-AES analysis of the filtrate of the standard reaction
(synthesis of 3a and 5a), also tested catalyst leaching after
completion of the reaction, a negligible amount of Cu (<2 ppm)
leached in the filtrate for both the cases. After completion of the
reaction catalyst was filtered, washed and calcined for recycling, and
it exhibited good reusability (table 5).
increase the yield of Glaser coupling product. The coupling of several
oxazolidinones and other nitrogen nucleophiles with various aryl and
alkyl acetylene derivatives were next investigated with our optimized
Table 4: Substrate scope of amidation a
O
O
Cu-MnO, O2
O
O
R1
N
R1
HN
R2
toluene, Na2CO3
100°C, 2h
R2
O
O
5a,
5b,
95%, R = H
91%, R = Me
, 93%, R = OMe
, 82%, R = NMe2
, 90%, R = tBu
88%, R = Br
O
5i,
96%, R = H
5j, 92%, R = Me
O
N
N
5k
5l
, 85%, R = OMe
, 82%, R = NMe2
5c
5d
5e
5f,
5g
5h
5m,
90%, R = F
Cl
Table 5: Reusability of the catalyst
R
R
, 90%, R = F
, 81%, R = CN
O
N
O
O
N
O
O
O
R
N
Ph
75%, R = Me
R
R1
O
5v
5u
5v,
5w
R
t 89%, R = Cl, R1 = H
, 81%, R = CF3, R1 = H
84%, R = OMe, R1 = H
5q
5r
5s,
, 78%, R = H
5n,
5o
5p,
, 80%, R = CH2Cl
, 82%, R = OMe
68%, R = Br
75%, R = Bn
, 85, R = OMe, R1 = CH2Cl
O
N
O
O
N
O
O
O
N
R
Ts
N
R
R
Catalyst was filtered and thoroughly washed with water and acetone, dried in
vacuum, followed by calcination at 350 C under 10% H2 in N2 flow, for 6h, then
reused.
OBz
5y
, 80%, R = H
5ac
5ad
, 85%, R = H
, 82%, R = CH2Cl
5aa
5ab
, 96%, R = H
, 90%, R = CH2Cl
5x
, 94%
5z
, 71%, R = CF3
a Standard reaction conditions: 0.25 mmol, amide 2 equiv, Na2CO3 2 equiv.; toluene
1 ml, 5% Cu-MnO catalyst 12 mg (3.75 mol% Cu), 100 C, in Air, for 2h
Kinetic study
In order to better understand the reaction profile, kinetic studies
were performed using phenylacetylene and diethyl H-phosphonate
as a reactant. The production of alkynylphosphonates and the Glaser
coupling product[54] diyne was monitored by HPLC analysis. When 2
equiv. of H-phosphonates (Fig 2a) was used reaction, the reaction is
very fast at the beginning, almost 75% product was obtained within
20 min, and the reaction was completed in 90 min, 94% of desired
alkynylphosphonates was obtained with ca. 2% diyne. Upon reducing
the amount of H-phosphonates to 1.2 equivalent (Fig 2b), within 10
min, 12% diyne and 55% of desired alkynylphosphonates were
identified. Finally, we have observed, with less amount of coupling
partner, increased the production of unwanted homocoupled dimer
product(~15%) and subsequently, the yield of desired product
diminished. In the case of ynamide synthesis (Fig. 2c and 2d), using
phenyl acetylene and oxazolidin-2-one as a substrate, a similar result
was observed, reducing the amount of N-nucleophile to 1.2
equivalent, increased the production of Glaser coupling diyne
product.[54] Also, the amidation reaction rate is little slower than the
phosphorylation reaction as observed from the reaction kinetics.
From the kinetic studies, it was confirmed that excess nucleophile is
required for both the reaction to prevent the homocoupled diyne
product formation.
condition. The results are summarized in Table 4. Aromatic alkynes
consisting with both electron donating and electron withdrawing
functional groups, such as Me, OMe, NMe2, tBu, Br, F, and CN on the
para-position of the phenyl ring reacted with oxazolidin-2-one very
well and produced the corresponding ynamide in good to excellent
yields (Table 4, entries 5a-5h). We have next investigated with other
cyclic carbamates like 4-(chloromethyl)oxazolidin-2-one and (S)-4-
benzyloxazolidin-2-one, showed similar reactivity and gave the
desired ynamides in good to excellent yields (entries 5i-5p). Other
aromatic alkynes, such as 2-Ethynyl-6-methoxynaphthalene reacts
well oxazolidin-2-one and derivatives and lead to good yields of
corresponding ynamides (entries 5q-5s). The substitution of the
functional group at ortho and meta position in the phenyl ring does
not have much effect in the coupling reactions, high yields of desired
ynamides were obtained (entries 5v-5x). Another nitrogen
nucleophile, N-Methyl-p-toluenesulfonamide also
a
viable
substrateand afforded ynamides in good yields (entries 5y-5z). Next,
we have investigated reaction scope with alkyl substituted terminal
alkynes with different oxazolidinone coupling partners, afforded
ynamides in good to excellent yields (entries 5aa-5ad).
The reaction with phenylacetylene and oxazolidinone are scaled up
to a gram scale, ynamides (5a) was successfully synthesized in
comparable yields (92%). Similarly, phosphorylation was also scaled
4 | J. Name., 2012, 00, 1-3
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Conclusions
Alkynylation of H-phosphonates
View Article Online
DOI: 10.1039/C9CY00275H
OEt
H
EtO
Ph
OEt
Cu-MnO, air
In conclusion, we have developed a very efficient and reusable
heterogeneous Cu-MnO catalyst for the aerobic oxidative coupling of
a terminal alkyne with H-phosphonates and amides to synthesis
alkynylphosphonates and ynamides respectively in excellent yields.
A variety of terminal alkynes included electron rich, and electron
poor aromatic, as well as aliphatic alkynes with several H-
phosphonates, delivered corresponding alkynylphosphonates in very
good to excellent yields. Our catalyst is highly reactive, as revealed
by kinetics study, for both the cases reaction time is shorter
compared to the literature report,[23-32, 49] where it takes mostly more
than 12h, but in our case reaction completed within 2h. The added
advantage is phosphorylation reaction is base and additive free. For
ynamides synthesis, a variety of terminal alkyne and different
oxazolidinones was successfully utilized and generated the desired
product in good to excellent yields. Other nitrogen nucleophile such
as N-Methyl-p-toluenesulfonamide also a viable substrate and
afforded C-N coupled product in good yields. This methodology could
be scaled up to gram scales and tolerate several functional groups.
In addition, the catalyst showed very good reusability, up to fifth
recycle it showed similar productivity.
H
P
OEt
P
+
+
O
DMSO
100°C
Ph
O
Ph
Ph
1.2 or 2 eq.
Synthesis of ynamides
O
O
O
Ph
H
Cu-MnO, O2
N
HN
+
O
+
Ph
toluene, Na2CO3
100°C
Ph
Ph
1.2 or 2 eq.
Conflicts of interest: There are no conflicts to declare
Experimental Section
Figure 2: Kinetics for alkynylation of H-phosphonates (a) with 2 equiv. H-
phosphonates (b) with 1.2 equiv. H-phosphonates and synthesis of ynamides (c)
with 2 equiv. amides (d) with 1.2 equiv. amides. Reaction progress was monitored
by HPLC
General procedure I for phosphorylation:
In a carousel reaction tube Cu-MnO catalyst (12 mg) was taken,
terminal alkyne (0.25 mmol), dialkyl phosphate (0.5 mmol) and 1 mL
DMSO was added over it. The reaction mixture was stirred at 100 C
for 1.5h under air atmosphere. After completion of the reaction, the
crude reaction mixture was filtered and washed with ethyl acetate
(25 mL). The organic layer was washed with water, and then the
water layer was re-extracted with ethyl acetate (2x 25 mL). The
combined organic layer was washed with brine solution, dried over
Na2SO4, and then concentrated under reduced pressure. The
resulting residue was purified by flash chromatography (ethyl
acetate: hexane) to afford the desired alkynylphosphonates.
To get some insight into the reaction mechanism, we have carried
out some controlled experiment. Both the reaction goes smoothly in
the presence of radical scavenger like BHT and TEMPO (Scheme 1, eq
1), the similar yield of the desired coupling product was observed,
which clearly indicates that reaction does not proceed through the
radical pathway. With decreasing the amount of phosphorylation or
amidation reagent, the yield of the C-P (60%) and C-N (51%) coupled
product decreases, whereas C-C homo-coupled Glaser coupling
product formation increases (19-24%) under this condition as
reported by others.[49] However, under complete inert conditions
both the reaction does not proceed, these results suggest that
oxygen is essential for these reactions.
General procedure II for Ynamide synthesis:
1) In presence of radical scavenger
In a carousel reaction tube, Cu-MnO catalyst (12 mg) and Na2CO3 (53
mg, 0.5 mmol) were taken, the tube was then evacuated and refilled
with oxygen three times. Next, the terminal alkyne (0.25 mmol),
oxazolidin-2-one (0.5 mmol) and 1 mL Toluene were added over it via
syringe. The reaction mixture was stirred at 100 C for 2h under an
oxygen atmosphere. After completion of the reaction, the crude
reaction mixture was filtered and washed with ethyl acetate (25 mL).
The organic layer was washed with water and brine solution, dried
over Na2SO4, and then concentrated under reduced pressure. The
resulting residue was purified by flash chromatography (ethyl
acetate: hexane) to afford the desired ynamides.
O
O
standard condition
desired product obtained
in similar yield
or
OEt
HP
EtO
HN
O
a) TEMPO
b) BHT
2) With lower amount (stoichiometric) P or N nucleophile
O
O
HP
EtO
1 equiv
standard condition
C-P pdt, 60%
or
OEt
HN
Dimer
O
or
C-N pdt, 51%
19-24%
1 equiv
1 equi.
3) Under the inert atmosphere
O
O
O
or
OEt
NR
HP
HN
Inert condition
EtO
1 equiv
1 equiv
Scheme 1: Control experiments to understand the mechanism
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Catalysis Science & Technology
Page 6 of 7
COMMUNICATION
Acknowledgments
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material synthesis and characetrization. We are also grateful to Dr.
S. Karan for his help in XPS analysis. The authors also acknowledge
the Analytical and Environmental Science Division and Centralized
Instrument Facility of CSIR-CSMCRI for all characterization. HS, TS,
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Page 7 of 7
Catalysis Science & Technology
View Article Online
Graphical abstract
DOI: 10.1039/C9CY00275H
Aerobic Oxidative Alkynylation of H-Phosphonates and Amides:
An Efficient Route for the Synthesis of Alkynylphosphonates and
Ynamides by Recyclable Cu-MnO Catalyst
Harshvardhan Singh, Tapan Sahoo, Chiranjit Sen, Sunil M. Galani and Subhash Chandra
Ghosh*
Developed a straightforward, atom-economical and scalable route for the synthesis of alkynylphosphonates and
ynamides using reusable Cu-MnO catalyst.