Alkali Metal Catalysed Double Hydrophosphorylation of Nitriles and Alkynes

Article abstract of DOI:10.1002/ejic.201900164

Catalytic C–P and N–P bond formation via double hydrophosphorylation of nitriles with diphenylphosphane oxide using alkali metal precatalyst [MN(SiMe₃)₂] (M = Li, Na, K) is reported. The potassium congener was observed to be the most

Full text of DOI:10.1002/ejic.201900164

A Journal of
Accepted Article
Title: Alkali Metal Catalysed Double Hydrophosphorylation of Nitriles
and Alkynes
Authors: Indrani Banerjee, Adimulam Harinath, and Tarun Kanti Panda
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10.1002/ejic.201900164
European Journal of Inorganic Chemistry
FULL PAPER
Alkali Metal Catalysed Double Hydrophosphorylation of Nitriles
and Alkynes
Indrani Banerjee,[a] Adimulam Harinath[a] and Tarun K. Panda* [a]
Dedicated to Prof. Kazushi Mashima on the occasion of his 62nd birthday.
as active metal catalysts in various applications is appealing
because of their low electronegativity and stable low oxidation
Abstract:
state.7 However, our research group has successfully
Catalytic C–P and N–P bond formation via double
explored various applications of alkali and alkaline earth metal
hydrophosphorylation of nitriles with diphenylphosphine oxide using
catalyst systems over the past few years.8
alkali metal pre-catalyst [MN(SiMe3)2] ( M = Li, Na, K) is reported. The
The use of group 1 and 2 metals has also not been explored in
potassium congener was observed to be the most efficient catalyst for
the synthesis of organophosphorus compounds from nitriles.
converting aryl nitriles to the corresponding N-((diphenyl-
Over the past few years, organophosphorus compounds have
phosphoryl)(aryl)methyl)-P,P-diphenylphosphinic amide [ArCHP(O)-
emerged as preeminent organic compounds and have received
Ph2NHP(O)Ph2] under mild temperature (60°C) and neat condition.
much attention due to their wide application in pharmaceuticals,9
Double hydrophosphorylation of alkynes with HP(O)Ph2 is also very
natural products10, and organic syntheses,11 as well as
effective when [KN(SiMe3)2] is used as a pre-catalyst at room
organometallic chemistry,12 as versatile catalysts and chelating
temperature, and gives the corresponding 1,2-diylbis(diphenyl-
ligands. The research with phosphines (R3P) and phosphine
oxides (R3P=O) (R = H, aryl, alkyl) for the formation of partially or
fully oxidised P–C–P and P–C(N)–P frameworks has received
considerable attention from synthetic chemists due to the robust
nature of the P=O double bond13 in phosphine oxides. Till date,
reports on metal-catalysed reactions of nitriles have been limited,
evoking significant research to develop potentially active catalysts.
phosphine oxide [RCHP(O)Ph2CH2P(O)Ph2] as the product. A wider
substrate scope of both reactions is explored.
Introduction
Transition metals are of great importance in organic chemistry.
For several years, they have been widely used in numerous
catalytic processes and are gradually expanding the growth of
organometallic chemistry.1 Several adjustments to transition
metal catalysts have led to the development of many important
reagents and significant reactions, which are well known from
textbooks.2 However, transition metal catalysts have certain
disadvantages: they are generally costly and toxic to a certain
extent. Removing deposits of some heavy metal residues from
the resulting products is quite challenging, although essential, in
medicinal chemistry.3 In a few cases, transition metal catalysts
require additives and co-catalysts to enhance the efficacy of
reactions.4 Also, excessive use of transition metal catalysts
does not lead to sustainable growth. Thus, an alternative
approach involving environment-friendly and atom-
economical chemical methods is much needed and has
become a recent trend in modern synthetic organic as well as
inorganic chemistry.5 This greener approach is aided by the
use of alkali and alkaline earth metals, owing to their low cost
and abundance in nature.6 They are also familiar in our
everyday lives because of their bio compatibility. They act as
highly reactive reagents in organic transformations, yet the
application of these metals has not been explored fully
because of their sensitivity towards air and moisture. Their use
Figure 1. Selective metal catalysts for double hydrophosphorylation of nitriles
and isonitriles.
Previously published reports suggest that the formation of 1,1-
addition products generating P–C–P linkage are easily
accessible.14 But very few reports have recognised 1,2-addition
hydrophosphorylated products with a P–C–N–P framework.
Storace et al. first noted that the formation of P–C–N–P linkage,
with low yields of double phosphorylated product, was extremely
useful for the human leukocyte elastase inhibitor.15 Very recently,
the lanthanum (III) metal complex was employed by Schmidt et al.
as an efficient catalyst for the hydrophosphorylation of a wide
range of nitriles to obtain both the 1,1 and 1,2-regioisomers in
good yield after extending the reaction times.16 Notably, various
reports also describe the utility of carbon–carbon unsaturated
systems for the synthesis of organophosphorus compounds
[a]
I. Banerjee, A. Harinath, Dr. T. K. Panda
Department of Chemistry, Indian Institute of Technology Hyderabad
Kandi – 502 285, Sangareddy, Telangana, India.
E-mail: tpanda@iith.ac.in
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10.1002/ejic.201900164
European Journal of Inorganic Chemistry
ARTICLE
mediated by alkali metal catalysts. Several reports have
recognised the synthesis of mono- or bis-alkenylphosphine
oxides.17 Very recently, Westerhausen et al. reported the
hydrofunctionalisation of alkyne derivatives via potassium
demesitylphosphinite as a catalyst.18 However, reports on double
phosphorylation of alkynes with P-C-C-P framework are scarce.
An air-induced metal and solvent–free protocol for the synthesis
of bisphosphinylethanes was established as a greener approach,
but the requirement of excess heating, as well as prolonged
reaction time, were disclosed as hindrances.19 Very recently,
transition metal–free procedures for the synthesis of
organophosphoryl compounds were achieved by t-BuOLi and t-
BuOK.20 Although the protocols were simple and clean, the
reaction required more time and a higher temperature.
All three alkali-metal were found to be active and we observed a
moderate yield of up to 79% using [KN(SiMe3)2] as the pre-
catalyst (Table 1, entries 1–3). However, when the catalyst
loading was raised to 20 mol %, all three Li, Na and K salts
exhibited greater reaction selectivity and consequently afforded
high yields (up to 96%) after one hour of reaction time (Table 1,
entries 4–6). Additionally, the double phosphorylation was
screened in the presence of various solvents such as toluene,
benzene, THF and hexane, and a slightly lower yield was
observed after one hour of reaction time (Table 1, entries 7–10).
In synthetic chemistry today, alkali-metal amides and
hexamethyldisilazides are the most commonly encountered
classes of reagents among alkali metal catalysts. Recently, the
efficiency of alkali-metal amides in various organic transformation
processes were reviewed by Mulvey and Robertson.21 Alkali-
metal amides are safer to handle and are more soluble in
hydrocarbon solvents, which render them better alternatives to
competing reagents such as alkali-metal hydrides and alkyl
reagents. We have recently reported that crossdehydrocoupling
(CDC) of hydrosilanes with amines,8h CDC of boranes and
amines8i, and CDC of hydrosilanes and alcohols8m can be easily
achieved using alkali-metal amides as pre-catalysts. However,
the use of alkali metals as pre-catalysts in the
hydrophosphorylation of nitriles has not been reported till date.
Easy availability, non-toxicity and economic viability of group 1
metal amides have induced us to examine their feasibility as pre-
catalysts in double hydrophosphorylation of nitriles as well
terminal alkynes with diphenylphosphine oxide. Here, we report
the facile synthesis of N-((diphenylphosphoryl)(aryl)methyl)-P,P-
diphenylphosphinic amide and (1-(aryl)ethane-1,2-diyl)bis-
(diphenylphosphine oxide) through double hydrophosphorylation
of aryl nitriles as well as alkynes by alkali hexamethyldilazides as
active catalysts under mild condition.
Scheme 1. Alkali metal–mediated double hydrophosphorylation of benzonitrile
with diphenylphosphine oxide.
Figure 2. 31P{1H} (left) and 1H (right) NMR spectra of doubly phosphorylated
product of benzonitrile and diphenylphosphine oxide.
Thus, with 60°C and neat condition as optimal conditions, we set
out to examine the scope of the substrates of various aryl nitriles
and diphenylphosphine oxide in the presence of 20 mol %
potassium hexamethyldisilazide. Results of the catalytic double
hydrophosphorylation reaction are displayed in Table 2.
Table 1. Screening of alkali-metal salts for double
hydrophosphorylation of benzonitrile and diphenylphosphine
oxide
Results and Discussion
Catalytic double hydrophosphorylation of benzonitrile with
diphenylphosphine oxide was carried out to examine the
efficiency of alkali-metal hexamethyldisilazides [MN(SiMe3)2] (M =
Li, Na, K) as pre-catalysts (Scheme 1). To our delight, we
observed the formation of the double hydrophosphorylated
product, which was confirmed by the 31P NMR spectrum depicting
the two characteristic doublets coupled with each other (Figure 2,
left). This indicates the formation of the new regioisomer with a
P–C–N–P framework, where one phosphine oxide is attached to
the carbon atom of the C≡N group while the other phosphine
oxide attaches to the nitrogen atom. The formation of the
characteristic –CH and –NH protons was also distinguishable
from the 1H NMR spectrum (Figure 2, right). Table 1 outlines the
primary results of the catalytic activity of three alkali-metal
hexamethyldisilazides [MN(SiMe3)2] (M = K, Na, Li) in the
selective formation of N-((diphenylphosphoryl)(phenyl)methyl)-
P,P-diphenylphosphinic amide from benzonitrile. In each case,
benzonitrile and diphenyl-phosphine oxide were used in a 1:2
molar ratio in the presence of 10 mol % of [MN(SiMe3)2] at 60°C.
Entry
Alkali metal
salts
Catalyst
loading
(mol %)
10
Medium
Time Isolated
(h)
yielda
(%)
65
1
2
3
4
5
6
7
8
9
LiN(SiMe3)2
NaN(SiMe3)2
KN(SiMe3)2
LiN(SiMe3)2
NaN(SiMe3)2
KN(SiMe3)2
KN(SiMe3)2
KN(SiMe3)2
KN(SiMe3)2
KN(SiMe3)2
Neat
Neat
Neat
Neat
Neat
1
1
1
1
1
1
1
1
1
1
10
10
20
20
20
20
20
20
70
79
86
92
Neat
96
96
Toluene
Benzene
THF
89
87
76
10
20
Hexane
Reaction conditions: Catalyst MN(SiMe3)2 (20 mol %), HP(O)Ph2
(0.502 mmol) followed by nitrile (0.251 mmol) in specified solvent
medium. aThe product was isolated from dichloromethane.
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10.1002/ejic.201900164
European Journal of Inorganic Chemistry
ARTICLE
Table 2. Substrate scope of various nitriles with
13
14
1.5
8
90
diphenylphosphine oxide for double hydrophosphorylation.
57b
15
8
Trace
Entry
1
Substrates
Time
(h)
Products
Yielda
(%)
1
96
Reaction conditions: Catalyst KN(SiMe3)2 (20 mol %), HP(O)Ph2
(0.502 mmol) followed by nitriles (0.251 mmol) in neat condition at
60°C. aIsolated yield. bThe reaction was carried out in toluene.
2
3
1.5
1.5
92b
91b
After the benchmark reaction of unsubstituted benzonitrile as the
substrate, which afforded a yield within one hour of reaction time
(Table 2, entry 1), we employed a range of aryl as well as
heterocyclic nitriles with electron-withdrawing and electron-
donating groups for the desired double hydrophosphorylation
under
optimal
conditions.
The
reaction
between
4
5
1
95b
93b
diphenylphosphine oxide and 4-chloro- or 4-bromo benzonitrile
afforded yields of 92% and 91% respectively within one-and-a-
half hours of reaction time (Table 2, entries 2–3). Similarly, the
reaction of substituted 4-trifluoromethyl benzonitrile and diphenyl
phosphine oxide gave a near-quantitative yield of the double
hydrophosphorylated product, 3d, within one hour of reaction time
(Table 2, entry 4). A yield of 93% of product 3e with good
functional group tolerance was achieved when the ester methyl 4-
1.5
6
7
3
3
86
92
cyanobenzoate was used as
a substrate to react with
diphenylphosphine oxide in the presence of a potassium catalyst
(Table 2, entry 5). The molecular structure of compound 3e was
confirmed by single-crystal X-ray diffraction analysis (Figure 3).
8
9
3
6
92
68b
10
11
8
8
53b
Figure 3. Solid-state structure of double hydrophosporylated product 3e
obtained from 4-cyanobenzoate and diphenylphosphine oxide.
Traceb
12
3
96
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10.1002/ejic.201900164
European Journal of Inorganic Chemistry
ARTICLE
(Scheme 2). Gratifyingly, we found that the potassium amide
[KN(SiMe3)2] catalyst remained highly efficient for the double
hydrophosphorylation of terminal alkynes too. The reaction for
double
hydrophosphorylation
of
phenylacetylene
with
diphenylphosphine oxide was carried out using [KN(SiMe3)2] as
the pre-catalyst in neat condition with a low catalyst loading of 5
mol % to give a near-quantitative yield within one-and-a-half hours
(Table 3, entry 1). The P–C–C–P linkage was verified by the 31
P
NMR spectrum, which depicts the attachment of two diphenyl-
phosphine oxide groups to the two adjacent carbon atoms of the
-C≡C- group (Figure FS 41 in ESI). The formation of the –CH
protons were also confirmed from 1H NMR (Figure FS 40 in ESI).
Thus, the scope of an array of terminal alkynes possessing
electron-withdrawing and electron-donating, as well as
heterocyclic and aliphatic groups, were analysed by 5 mol %
catalyst loading at room temperature, and the results are set out
in Table 3.
Figure 4. Solid-state structure of double hydrophosporylated product 3l
obtained from picolinonitrile and diphenylphosphine oxide.
This protocol was also found to be very effective and interesting
results were obtained from using electron-donating functional
groups with benzonitriles, although it required slightly longer
reaction time of three hours (Table 2, entries 6–10). 4-
Methylbenzonitrile and 4-(tert-butyl)benzonitrile yielded the
corresponding double hydrophosporylated products 3f (86%) and
3g (92%) within three hours (Table 2, entries 6–7). Product 3h
was also isolated in excellent yield (92%) by using 4-
methoxybenzonitrile as the substrate under optimised condition
(Table 2, entry 8). However, the reaction with 4-
(methylthio)benzonitrile was sluggish and yielded 68% of 3i
(Table 2, entry 9) even after 6 h of the reaction time. The reaction
of 4-dimethylamino benzonitrile with diphenylphosphine oxide
was also sluggish and only 53% was isolated after eight hours of
reaction time (Table 2, entry 10). Further, a bulkier substrate such
as 1-napthonitrile showed only trace amounts of reactivity with
diphenylphosphine oxide even after eight hours of reaction time
(Table 2, entry 11). To our delight, however, excellent yields were
obtained when heterocyclic nitriles such as picolinonitrile and
thiophene-2-carbonitrile were used as substrates. Both reactions
were accomplished to give near-quantitative yields of 96% and
90% within three and one-and-a-half hours respectively (Table 2,
entries 12–13). The bisphosphorylated product 3l was also
confirmed from single-crystal X-ray diffraction analysis (Figure 4).
It is noteworthy that when 2-(4-fluorophenyl)acetonitrile was used
as the substrate, a lower yield (57%) of the desired product was
achieved even after a prolonged reaction time of eight hours
(Table 2, entry 14), indicating the limitation of the catalyst. The
efficiency of the potassium catalyst was also examined on an
aliphatic nitrile such as chlorobenzonitrile, and only trace amounts
of the product were obtained after eight hours of reaction time
(Table 2, entry 15). Thus, the aliphatic nitriles could not be
converted to the corresponding doubly phosphorylated product,
perhaps due to the poor electrophilicity of the nitrile carbon atom
in the aliphatic nitrile, when compared to aryl nitriles.
Scheme 2. Alkali metal mediated double hydrophosphorylation of
phenylacetylene with diphenylphosphine oxide.
Table 3. Substrate scope of various terminal alkynes with
diphenylphosphine oxide for double hydrophosphorylation.
Entry
1
Substrates
Time
(h)
Products
Yielda
(%)
1.5
95
2
3
4
5
1.5
1.5
2
92
93b
87
1.5
91b
6
6
59
7
8
1.5
6
92
Double hydrophosphorylation of terminal alkynes
Inspired by the results of double hydrophosphorylation of aryl
nitriles as described above, we wanted to explore further the
scope of double hydrophosporylation with terminal alkynes using
a similar protocol for the synthesis of the 1,2-regiosiomer product
65c
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10.1002/ejic.201900164
European Journal of Inorganic Chemistry
ARTICLE
9
6
6
57d
54d
10
Reaction conditions: Catalyst KN(SiMe3)2 (5 mol %), HP(O)Ph2
(0.502 mmol) followed by terminal alkynes (0.251 mmol) in neat
condition at rt. aIsolated yield. bReaction was carried out in toluene.
d
cReaction was carried at 70°C. Catalyst KN(SiMe3)2 (5 mol %),
HP(O)Ph2 (0.502 mmol) followed by 4h (0.753 mmol) in neat
condition at 50°C.
The p-fluoro and p-bromo phenylacetylene were subjected to
hydrophosphorylation and yielded corresponding products in
excellent quantities (92% and 93% respectively) within one-and-
a-half hours at room temperature (Table 3, entries 2–3). Thus,
electron-withdrawing groups have proved their efficacy in near-
quantitative conversion of both nitriles and alkynes to the desired
product in excellent yields. The reaction protocol was also applied
to electron-donating groups on phenylacetylene and astounding
results were obtained within short reaction times for 4-methyl
phenylacetylene and 4-methoxy phenylacetylene, furnishing 87%
and 91% of the 1,2-regioisomer product respectively (Table 3,
entries 4–5). Bishydrophosphorylation was also explored on a
heterocyclic group such as 3-ethynylthiophene and 2-
ethynylpyridine, excellent to moderate yields of 92% and 59%
respectively (Table 3, entries 6 - 7) were obtained. The scope of
aliphatic alkynes such as cyclohexylacetylene, 1-hexyne and 1-
pentyne was probed for double hydrophosprylation and we
observed only sluggish reactions at room temperature in these
cases. But heating the reaction mixtures at 70°C for six hours
produced moderate yield. Cyclohexylacetylene on heating
produced a yield 65% of the desired product (Table 3, entry 8).
While aliphatic 1-hexyne and 1-pentyne produced a much lower
yield of 57% and 54% yields of the corresponding 1,2-addition
products (Table 3, entries 9–10). This confined the scope of
double phosphorylation of aliphatic alkynes using the potassium
catalyst.
Scheme 3. Most plausible mechanism for double hydro-phosphorylation of
nitriles and alkynes with diphenylphosphine oxide.
Further reaction with [HP(O)Ph2] yields the five-membered doubly
phosphorylated species (III), which undergoes rearrangement
and a second nucleophilic attack on the alkenyl/iminate carbon to
give species (IV). In the final step, a third molecule of [HP(O)Ph2]
undergoes protonolysis to produce the 1,1-regioisomer, which
further isomerises itself yielding the corresponding 1,2-
regioisomer product while regenerating the active metal catalyst.
Conclusions
We have described here the use of innocuous and bio-
compatible alkali metal hexamethyldisilazides [MN(SiMe3)2]
as competent pre-catalysts for the synthesis of a series of
organo-phosphorus compounds through chemoselective
catalytic double hydrophosphorylation of aryl nitriles and
terminal alkynes with diphenylphosphine oxide, using a
simple but highly efficient protocol. This protocol implies a
facile and atom-economical access to organophosphorus
compounds. The good functional group tolerance and
economic viability of the alkali metal catalyst makes it one of
the most versatile alternatives for the synthesis of an
organophosphorus compound scaffold.
Most Plausible mechanism:
Scheme 3 describes the most plausible mechanism for the double
hydrophosphorylation of -C≡N and -C≡C- groups and
diphenylphosphine oxide mediated by alkali metal hexamethyl-
disilazides. This mechanism is based on group 1 and group 3
metal–catalysed hydrophosphorylation of alkynes reported
recently by Westerhausen and Schmidt respectively.16,18 In the
first step, [KN(SiMe3)2] reacts with diphenylphosphine oxide to
give potassium diphenylphosphinite [KP(O)Ph2] (I) via the
removal of HN(SiMe3)2, and [KP(O)Ph2] (I) acts as the catalytically
active species. In the next step, potassium diphenylphosphinite
adds to the CX (X = N or -CH) triple bond, yielding potassium
alkenyl or iminate complex (II), which can be stabilised by
delocalising the positive charge with the phenyl groups present in
the nitriles and alkynes.
Experimental Section
General consideration
All manipulations involving air- and moisture-sensitive compounds were
carried out under argon using the standard Schlenk technique or argon-
filled M. Braun glove box. Hydrocarbon solvents (n-hexane, toluene,
benzene) were distilled under nitrogen atmosphere from LiAlH4 and stored
inside the glove box. THF was dried and deoxygenated by distillation over
sodium benzophenone under argon and then distilled and dried over CaH2
prior to being stored in the glove box. 1H NMR (400 MHz), 31P{1H} (161.98
MHz) and 13C{1H} (100 MHz) spectra were recorded on the BRUKER
ADVANCE III-400 spectrometer. Diphenylphosphine oxide was purchased
from TCI Chemicals (India) Pvt. Ltd transferred to the glove box and used
without any further purification. All nitriles and alkynes were purchased
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10.1002/ejic.201900164
European Journal of Inorganic Chemistry
ARTICLE
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from Sigma Aldrich, Alfa Aesar or TCI Chemicals (India) Pvt. Ltd and
stored in the glove box. LiN(SiMe3)2, NaN(SiMe3)2 and KN(SiMe3)2 were
purchased from Sigma Aldrich and used as received. NMR solvent (CDCl3)
was purchased from Merck and distilled over molecular sieves.
Typical procedure for catalytic double hydrophosphorylation of
nitriles. All catalytic reactions were performed using the following
standard protocol. In the glove box, the preferred catalyst KN(SiMe3)2 (20
mg, 0.100 mmol, 20 mol %) and diphenylphosphine oxide (101 mg, 0.502
mmol) were added to a Schlenk tube followed by the addition of nitriles
(0.251 mmol). The Schlenk tube was taken out and the reaction mixture
was stirred in an oil bath at the desired temperature. After the desired
reaction time, the reaction mixtures were subjected to evaporation under
reduced pressure. The crude mixtures were washed with hexane three
times (3 x 3 mL) prior to quenching by an aqueous medium. The aqueous
layer was extracted using dichloromethane. The combined organic layers
were dried over Na2SO4 and concentrated in vacuo, yielding white solid
products. The yields were calculated after isolating the products.
Crystallographic data (excluding structure factors) for complex 3e and 3l have
been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 1869185 (3e) and 1869184 (3l)
respectively. See SI for details.
Supporting information summary
Data for 3a, 3b, 3d, 3g, 3h, 3i, 3j, 3k and 5a, 5d, 5e, 5f are already
described in literature.16,19,20a Crystallographic data of 3e and 3l
and 1H, 13C{1H} and 31P{1H} NMR spectra of bis-
hydrophosphorylated products, 3a–3o and 5a–5j are given in the
electronic supporting information.
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Acknowledgments
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Keywords: Alkyne • Alkali metal • Hydrophosphorylation • Nitrile
• Diphenylphosphine oxide
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European Journal of Inorganic Chemistry
ARTICLE
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10.1002/ejic.201900164
European Journal of Inorganic Chemistry
ARTICLE
Entry for the Table of Contents
FULL PAPER
Doublehydrophosphoryla-
tion of nitriles and terminal
alkynes with diphenylphos-
phine oxide with high yield
and chemo-selectivity for
the production of organo-
Indrani Banerjee, Adimulam
Harinath and Tarun K.
Panda*
Page No. – Page No.
phosphorus
compounds
Alkali Metal Catalysed
Double Hydrophosphory-
lation of Nitriles and
Alkynes
using alkali metal salts
[MN(SiMe3)2] (M = Li, Na, K)
as pre-catalysts, and under
ambient conditions are
reported.
This article is protected by copyright. All rights reserved.