Ionic Liquid-Promoted Phospha-Michael Reaction: Convenient Access to β-Nitrophosphonates

Article abstract of DOI:10.1080/00397911.2015.1064138

A convenient and mild procedure is developed for β-nitrophosphonates via phospha-Michael addition of phosphites to nitrostyrene at room temperature in the presence of 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU)-based ionic liquid [DBUH][OAc]. The operationa

Full text of DOI:10.1080/00397911.2015.1064138

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Ionic Liquid–Promoted Phospha-Michael Reaction:
Convenient Access to β-Nitrophosphonates
S. H. Jayaprakasha, B. Satheesh Krishnaa, S. Santhi Sudhaa, N. Bakthavatchala Reddya, P.
Sreelakshmia, K. Madhu Kumar Reddya & C. Suresh Reddya
a Department of Chemistry, Sri Venkateswara University, Tirupati, INDIA
Accepted author version posted online: 25 Jun 2015.
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To cite this article: S. H. Jayaprakash, B. Satheesh Krishna, S. Santhi Sudha, N. Bakthavatchala Reddy, P. Sreelakshmi, K.
Madhu Kumar Reddy & C. Suresh Reddy (2015): Ionic Liquid–Promoted Phospha-Michael Reaction: Convenient Access to β-
Nitrophosphonates, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, DOI: 10.1080/00397911.2015.1064138
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Ionic Liquid–Promoted Phospha-Michael Reaction: Convenient Access to β-
Nitrophosphonates
S. H. Jayaprakash1, B. Satheesh Krishna1, S. Santhi Sudha1, N. Bakthavatchala Reddy1,
P. Sreelakshmi1, K. Madhu Kumar Reddy1, C. Suresh Reddy1,
1Department of Chemistry, Sri Venkateswara University, Tirupati, INDIA
Corresponding Author C. Suresh Reddy, E-mail: csrsvu@gmail.com
Abstract
A convenient and mild procedure is developed for β-nitrophosphonates via Phospha-
Michael addition of phosphites to nitrostyrene at room temperature in the presence of 1,8-
diazabicyclo- [5.4.0]undec-7-ene (DBU) based ionic liquid [DBUH][OAc]. The
operational simplicity, convenient work-up, and reusability of the ionic liquid makes this
method attractive.
KEYWORDS: Phospha-Michael addition, Ionic Liquid, [DBUH][OAc], C-P bond
formation
INTRODUCTION
Chemistry of organophosphorus compounds continues to gain an increasing interest in
the development of new methodologies for their preparation, owing to the biological,
agricultural and organic synthesis.[1-4] Efforts to formulate more efficient procedures
1

remain an important goal in organic synthesis. Construction of carbon-phosphorus (C-P)
bond is one the most important synthetic step since they produce α- and β-functionalized
phosphonic acid/ ester and their derivatives which serve valuable intermediates for the
preparation of bioactive compounds.[5] Several C-P bond forming methodologies such as
Michaelis-Arbuzov, Kabachnik-Fields, Pudovik reaction and Phospha-Michael reaction
have been reported for the synthesis of different class of important organophosphorus
compounds.[6–9]
Conjugate addition of phosphorus nucleophile (Michael donor) to activated olefins
(Michael acceptor) is called Phospha-Michael reaction.[10,11] Among the various Michael
acceptors, nitro alkenes are very attractive because the nitro group being the strong
electron-withdrawing group induces generation of electrophilic center at its β-carbon.[12]
The nucleophile facilitates addition of phosphorus at it forming C-P bond. Thus
conjugate addition of phosphonates to nitroolefins is a convenient method for the
synthesis of β-nitrophosphonates, which are precursors for the preparation of β-
aminophosphonic acids.[13] In recent years, β-aminophosphonic acids received
considerable attention due to their increasing applications in peptide and medicinal
chemistry. They serve as the surrogates of β-amino acids in peptides and peptidomimetics
with significantly improved bioactivities and pharmaco kinetic properties.[14,15] Though
there are considerable number of reports on the development of new synthetic
methodologies for β-nitrophosphonates,[16-19] the majority of these are suitable only for
diaryl phosphite but not for dialkyl phosphites. Hence there is a necessity to develop an
efficient and eco-friendly method applicable for both alkyl and aryl phosphites.
2

Ionic liquids (ILs) have become the choice of organic green chemical synthesis, due to
their distinctive properties, such as good thermal stability, negligible vapour pressure,
ease of handling, potential for recycling, good solubilizing capability.[20-22] 1,8-
Diazabicyclo[5.4.0]undec-7-ene acetate [(DBUH)(OAc)] being very useful as a non-
nucleophilic task-specific organic ionic base[23-24] is successfully used as both reaction
medium and catalyst for the synthesis of β-nitrophosphonates.
RESULTS AND DISCUSSION
Reaction of nitrostyrenes (2a-h) and phosphites (1a-c) at room temperature in the
presence of [DBUH][OAc] ionic liquid (3) afforded β-nitrophosphonates (4a-r) in good
yields (Scheme 1).
To establish the suitable reaction conditions, we have chosen the reaction between
p-N, N-diethyl nitrostyrene, dimethyl phosphite as a model reaction (Table 1). It was
carried by using various catalysts and catalyst free conditions at room temperature. The
reaction did not progress with PPh3, TBAc and catalyst free conditions (Table 1, Entries
4, 6 & 1). Lewis bases DMAP, DBU and TBAB produced low product yields (Table 1,
Entries 2, 3 & 5). But DBU derived ILs (Table 1, Entries 11-13) offered good yields
compared to other ionic liquids (Table 1, Entries 7-10). Although DBU derived ILs such
as [DBUH][OAc], [DBUH][Lac] and [DBUH][Tfa] have the same cation [DBUH]+, they
showed the catalytic activities in the order: [DBUH][OAc] > [DBUH][Lac] >
[DBUH][Tfa]. This suggests that the anions of the ILs show significant effect on the
activities of the ILs for catalyzing this reaction. Even though [bmim][OAc] (Table 1,
3

Entry 10) catalyzes this reaction, the reaction was sluggish and the product yields were
low when compared to [DBUH][OAc] (Table 1, Entry 13). This implies that the cation
part of the ILs exhibit considerable impact on the activities of the ILs for catalyzing this
reaction. From the above results, it is deduced that both the cation and the anion of the IL
plays important roles in catalyzing the reaction of phosphites with nitrostyrenes. So we
have chosen [DBUH][OAc] as catalyst for the preparation of title compounds.
Further we studied the influence of catalyst concentration, temperature and reaction time
for the model reaction. Increasing the catalyst concentration failed to improve the yield
(Table 1, Entries 15, 16), while decreasing the catalyst concentration led to reduced yield
(Table 1, Entries 14). The best results were obtained by performing the model reaction in
the presence of 10 mol% of catalyst to yield the product in good yield. By elevating the
temperature up to 70 °C, the yield remained unchanged (Table 1, Entries 17-19).
Therefore, the optimum conditions for this reaction were: 10 mol% of catalyst at room
temperature under solvent-free condition.
In order to establish the generality of this methodology, the synthesis of a variety of β-
nitrophosphonates in the presence of [DBUH][OAc] ionic liquid under the optimized
reaction conditions was investigated. The results of these studies are summarized in
Table 2. The effect of the substituents on the phenyl ring of the nitrostyrenes was also
investigated. Aliphatic nitrostyrene (2h) exhibited low reactivity towards phosphites and
produced low product yield. Heterocyclic nitrostyrene (2g) and nitrostyrenes containing
electron withdrawing groups (2e & 2f) showed moderate reactivity towards phosphites
4

and produced moderate product yield. While simple phenyl nitrostyrenes (2a) and
nitrostyrenes having electron donating groups (2b, 2c & 2d) exhibited good reactivity
towards phosphite nucleophiles and consequently produced good product yields. The
catalyst was compatible with functional groups such as Br, CN and -OMe. No
competitive nucleophilic methyl ether cleavage was observed for the substrates which
possessed -OMe group (Table 2, Entries 7-9), despite the strong nucleophilicity of
phosphites.
From the experimental results it was noticed that diphenyl phosphite showed good
nucleophilic character and produced good product yields, whereas diethyl and dimethyl
phosphites displayed moderate nucleophilic character and gave moderate yields. The
difference in the product yields may be explained on the basis of acidity of the
phosphites. It was reported that pentavalent phosphorus remains in equilibrium with
trivalent phosphorus which is attacking species at the carbon electrophilic center of the
olefin, shown in Scheme 2.[25] This equilibrium is highly influenced by the acidity of the
phosphite. Phosphite with increasing acidic character shifts the dynamic equilibrium
towards the formation of trivalent state (III) as a result the rate of nucleophilic addition to
the olefinic carbon reaction increases. For this reason diphenyl phosphite with pKa value
9.0 acts as a good nucleophile while dimethyl phosphite having pKa value 18.4 is not.
A plausible mechanistic route for this reaction is proposed in Scheme 3. Initially,
nitrostyrene (2a-h) abstracts a proton from ionic liquid (3) to form the intermediates (IV)
and (V).[26] Intermediate (V) subsequently undergoes a Michael-type addition with
5

phosphite (1a-c) followed by proton shift provides the intermediate (VII) which loses a
proton to the intermediate (IV) to regenerate the catalyst (3) and forms the desired β-
nitrophosphonates (4a-l).
The reusability of the catalyst is an important factor from the economic and
environmental point of view. Hence we investigated the possibility of reusability of the
recycled catalyst [DBUH][OAc]. Catalytic activity of the recovered ionic liquid from the
model reaction was checked in the subsequent runs (Figure 1). Our analysis and results
reveal that ionic liquid can be reused multiple times even though there is much less loss
in its activity.
In comparison with other catalysts employed for the model reaction, [DBUH][OAC]
showed a much higher activity in terms of short reaction time and mild conditions (Table
3).
EXPERIMENTAL SECTION
General
Solvents and reagents were procured from Sigma-Aldrich & Merck and are used
as such without further purification. Melting points were determined using a calibrated
thermometer by Guna Digital Melting Point apparatus. IR spectra were recorded on FT-
IR spectrometer. 1H and 13C spectra were recorded as solutions in CDCl3 on a Bruker
AMX 500 MHz spectrometer operating at 300 MHz for 1H, 75.4 MHz for 13C and 120
MHz for 31P NMR. For 1H and 13C chemical shifts tetramethylsilane (TMS) was taken as
6

an internal standard and 85 % H3PO4 was taken as an external standard for 31P chemical
shifts. ESI mass spectra were recorded on a Micromass Quattro LC instrument. Elemental
analysis was performed on Thermo Finnegan Instrument.
General Procedure For Preparation Of Ionic Liquid [DBU][Ac]
[DBUH][OAc] ionic liquid was prepared according to the reported procedures.[23] In a 50
mL two necked round bottomed flask, one neck was blocked with nitrogen trap to
maintain inert atmosphere and DBU (1 equiv.) was loaded through other neck. To this
acetic acid (1 equiv.) was added drop wise over a period of 15 min with stirring.
Throughout this addition the temperature was maintained between 0-5 °C. The resultant
mixture was stirred overnight at 60 °C, after completion of the reaction a light yellow
viscous oily liquid was obtained. Thus obtained oily residue was dried in vacuo at 60 °C
for 12 h to afford [DBU][Ac] a light yellow viscous liquid.
Characterization data for [DBUH][OAc]: Light yellow viscous oily liquid, 1H NMR (400
MHz, D2O): δ 1.76 (s, 3H, CH3), 1.52-1.67 (m, 6H), 1.84-1.90 (m, 2H), 2.39-2.65 (m,
2H), 3.16-3.19 (m, 2H), 3.28-3.44 (m, 4H); 13C NMR (100 MHz, D2O): δ 19.5, 23.3,
25.9, 27.3, 28.4, 32.8, 38.0, 48.2, 54.1, 165.9, 179.4.
General Procedure For The Synthesis Of Β-Nitrophosphonates (4a-L)
In a typical experiment to synthesize β-nitrophosphonates (4a-r), nitrostyrene (2a-
h, 1.0 mmol), phosphite (1a-c, 1.2 mmol) and the ionic liquid [DBUH][OAc] with the
desired amount (10 mol %) were loaded into the reaction flask and stirred magnetically.
After completion of the reaction, water was added to the reaction mixture and the
7

products were extracted with ethyl acetate (3X15 mL). The combined ethyl acetate
extract was dried over anhydrous Sodium sulphate (Na2SO4) and then concentrated
through vacuum evaporation to obtain the crude product, which was further purified by
column chromatography. The aqueous layer consists of [DBUH][OAc]. Water was
evaporated under reduced pressure to recover the ionic liquid which was reused to
perform the
Dimethyl (1-(4-(diethylamino)phenyl)-2-nitroethyl)phosphonate (4e): Yellowish
liquid, Isolated yield = 88 %; IR: ν = 3026, 2893, 1641, 1581, 1324, 1162 cm-1; 1H NMR
(300 MHz, CDCl3): δ 7.10-6.60 (m, 4H, Ar), 4.89-4.85 (m, 2H, CH2), 3.96-3.89 (m, 1H,
CH), 3.74-3.71 (d, J=10.8 Hz, 3H, OCH3), 3.54-3.52 (d, J=10.5 Hz, 3H, OCH3), 3.34-
3.30 (q, J=7.01 Hz, 4H, 2CH2), 1.14 (t, J=7.09 Hz, 6H, 2CH3); 13C NMR (75.4 MHz,
CDCl3): δ 146.4, 127.4, 122.4, 112.9, 69.3, 56.4, 54.7, 48.2, 47.6, 38.7, 16.3, 15.8; 31P
NMR (120 MHz, CDCl3): δ 22.73; MS (ESI): m/z 331 [M+H]+; Anal. Calcd.for
C14H23N2O5P: C, 50.91; H, 7.02; O, 24.22; Found: C, 50.73; H, 6.85; O, 24.11.
CONCLUSION
We have developed a neat and environmentally benign procedure for the construction of
C-P bond. [DBU][AC] ionic liquid was used as an efficient catalyst for synthesis of
β-Nitrophosphonates by the reaction of nitro olefins and dialkyl/aryl phosphites at room
temperature under solvent-free conditions. The method is applicable for various
Nitrostyrenes and afforded the corresponding β-Nitrophosphonates in moderate to good
8

yields. The use of green, nontoxic, economical and reusable catalyst [DBUH][OAC] is
the merit of this procedure.
CONFLICT OF INTEREST
We state that none of the authors have any conflict of interest in the context of this
communication.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
ACKNOWLEDGEMENTS
We thank Prof. C.D. Reddy, Department of Chemistry, Sri Venkateswara
University, Tirupati, for his helpful Discussions, University Grants Commission (UGC),
New Delhi for providing Senior Research Fellowship to one of the author Mr. S.H.
Jayaprakash and for funding a major research project (F. No.: 42-281/2013 (SR), dated:
12-03-2013).
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12

Table 1. Optimization of the model reaction under various conditionsa
Entry
1
Catalyst (mol%)
No catalyst
Temp (°C)
Time (hrs)
10.0
8.0
Yield (%)b
NRc
33
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
50
60
2
DMAP(10)
3
DBU(10)
8.0
52
4
PPh3 (10)
10.0
8.0
NRc
26
5
TBAB (10)
6
TBAc(10)
8.0
NRc
41
7
[bmim]HSO4(10)
[bmim][BF4] (10)
[bmim][Cl] (10)
[bmim][OAc] (10)
[DBU][Lac] (10)
[DBU][Tfa] (10)
[DBUH][OAc] (10)
[DBUH][OAc] (5)
[DBUH][OAc] (20)
[DBUH][OAc] (30)
[DBUH][OAc] (10)
[DBUH][OAc] (10)
6.0
8
6.0
28
9
6.0
37
10
11
12
13
14
15
16
17
18
6.0
62
6.0
83
6.0
78
6.0
88
9.0
79
9.0
88
9.0
88
9.0
88
12
88
13

19
[DBUH][OAc] (10)
70
12
88
aReactions conditions: N, N-diethyl-4-(2-nitrovinyl) aniline (1 mmol), dimethyl
phosphite (1.2 mmol), solvent-free condition.
bIsolated yield
cNo Reaction.
14

Table 2. Scope for [DBUH][OAc] catalyzed synthesis of β-Nitrophosphonatesa
Entry
1
2, Ar
1,R
4
Yield (%)b
89
2a, Ph
la, Ph
lb, Et
lc, Me
lb, Et
lc, Me
la, Ph
la, Ph
lb, Et
lc, Me
la, Ph
lb, Et
lc, Me
lb, Et
lc, Me
lb, Et
lc, Me
lb, Et
lc, Me
4a
4b
4c
4d
4e
4f
2
2a, Ph
83
3
2a, Ph
81
4
2b, 4-N(Et)2C6H4
2b, 4-N(Et)2C6H4
2c, 4-MeC6H4
2d, 4-MeOC6H4
2d, 4-MeOC6H4
2d, 4-MeOC6H4
2e, 3-BrC6H4
2e, 3-BrC6H4
2e, 3-BrC6H4
2f, 4-CNC6H4
2f, 4-CNC6H4
2g, Thiophen-2-yl
2g, Thiophen-2-yl
2h, Me2CH
89
5
88
6
91
7
4g
4h
4i
86
8
83
9
82
10
11
12
13
14
15
16
17
18
4j
79
4k
41
4m
4n
4o
4p
4q
4r
78
76
78
77
78
75
58
2h, Me2CH
51
aReactions conditions:Nitro styrene (1 mmol), dimethyl phosphite (1.2 mmol),
[DBUH][OAc] IL (10 mol %) at RT and solvent-free conditions.
bIsolated yield
15

Table 3. Influence of different catalysts on the synthesis of Diphenyl (2-nitro-1-
phenylethyl)phosphonate (4a)
Entry Catalyst
Reaction conditions Time (h/min) Yield (%)a
1
2
3
4
TBD
THF/ rt
5min
0.5h
90[17]
79[19]
82[16]
89[b]
Quinidine thiourea/ 4Å MS DCM/ 5 °C
Quinine
Xylene/ -55 °C
6days
6.0h
[DBUH][OAC]
Neat/ rt
aIsolated yield
bPresent work
16

Figure 1. Recycling studies of [DBUH][OAc].
17

Scheme 1. Synthesis of β-nitrophosphonates (4a-l)
18

Scheme 2. Equilibrium between penta and trivalent phosphorus
19

Scheme 3. Mechanism for the formation of β-nitrophosphonates
20