Synthesis of α-aminophosphonates using solvate ionic liquids

Article abstract of DOI:10.1039/c7ra04407k

A range of α-aminophosphonates were accessed in high yields and very rapidly, using solvate ionic liquids as the reaction media. Reactions typically required less than 10 minutes to go to completion and precipitation of these products into water excludes the use of traditional work up procedures, giving the products in very high crude purity. Excellent functional group tolerance for both the aldehyde and amine reaction partners was observed, and a range of bis-aminophosphonates derived from aromatic diamines were also accessed in high yield and purity.

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Synthesis of a-aminophosphonates using solvate
ionic liquids†
Cite this: RSC Adv., 2017, 7, 27900
*
Daniel J. Eyckens and Luke C. Henderson
A range of a-aminophosphonates were accessed in high yields and very rapidly, using solvate ionic liquids as
the reaction media. Reactions typically required less than 10 minutes to go to completion and precipitation
of these products into water excludes the use of traditional work up procedures, giving the products in very
high crude purity. Excellent functional group tolerance for both the aldehyde and amine reaction partners
was observed, and a range of bis-aminophosphonates derived from aromatic diamines were also accessed
in high yield and purity.
Received 19th April 2017
Accepted 18th May 2017
DOI: 10.1039/c7ra04407k
rsc.li/rsc-advances
pose several problems: disposal of heavy metals and the reac-
tion solvent, the high toxicity of these materials, their sensitivity
Introduction
to atmospheric conditions, and their expensive nature.
a-Aminophosphonates are of great interest to organic chemists
as they have vast applications in elds such as medicine,1–10
agriculture, and in environmental decontamination.5,11,12 They
are considered phosphorus analogues to a-amino acids and the
phosphorus' geometry has served as a useful tool in medicinal
chemistry.13–16
The synthesis of these compounds via the Kabachnik–Fields
or Pudovik reaction (Scheme 1) is relatively straight forward,
using nucleophilic attack of di-alkyl or -aryl phosphite with an
imine.12 The imine species can be generated in situ, as part of
a three-component reaction, or preformed and added to the
phosphite, both methodologies have been presented in the
literature.12 Additionally, several reports employ excess of the
amine or dialkyloxy-phosphite (in some cases both) which
limits the broad appeal of this reaction.
Ionic liquids (ILs), in their many forms, have been used in
many areas of chemistry from materials science through to
solvents to facilitate organic transformations.23–29 The use of ILs
as solvents for this reaction have been reported with some
excellent results,30–34 particularly for the pseudo-ionic liquid
5.0 M lithium perchlorate in dithethyl ether (5 M LPDE), or the
use of LiClO4 as an additive to the reaction mixture.18,35–40 These
reactions were able to isolate a-aminophosphonates in very
high yield using reaction times under 1 hour.
Despite these benets, the use of 5.0 M LPDE as the reaction
media experiences several limitations, which include: enhanced
sensitivity to atmospheric conditions, problematic solvent
preparation, inabilÀity to be heated (due to potential explosive
nature of the ClO4 anion), and reagent restriction as not all
reagents will be soluble in the pseudo-ionic liquid. Also, while
the use of ionic liquids is an improvement over the use of metal-
based catalysts, these procedures still use large amounts of
organic solvent in the recovery and purication of the syn-
thesised phosphonate. Accessing these compounds in high
yield, short reaction time, and with minimal purication
remains a challenge in organic synthesis.
A large amount of work has been focused on optimizing the
synthesis of these molecules using a variety of Lewis acid
catalysts,17,18 such as CeCl3–proline complex,19 GaI3,20 In(OTf)3,
YbCl3, SmI2, MoO2Cl2,21 Sc(OTf)3, and Dy(OTf)3 (ref. 12) among
others.19,22 These efforts have given a variety of means to access
these compounds, though the use of these Lewis acids always
We recently reported the use of solvate ionic liquids (SILs),
being equimolar mixtures of LiTFSI in tri- or tetra-glyme
(referred to as [G3(Li)]TFSI or [G4(Li)]TFSI, respectively), as
suitable reaction media for electrocyclisation reactions and
characterised them using Kamlet–Ta parameters (Fig. 1).41,42
Indeed these solvate ionic liquids serve as a stable and easily-
handled surrogate to 5.0 M LPDE, while oen giving superior
reaction outcomes. They are able to be heated without concern,
present minimal toxicity,43 are simple and cheap to produce,
and can be stored over molecular sieves to maintain their
anhydrous nature, if required. This work sought to determine if
the synthesis of a-aminophosphonates could be successfully
Scheme
aminophosphonates.
1 Common approaches to the synthesis of a-
Institute for Frontier Materials, Deakin University, 75 Pigdons Road, Geelong, Victoria,
3216, Australia. E-mail: luke.henderson@deakin.edu.au
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c7ra04407k
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Table 1 Optimisation of a-aminophosphonate synthesis
carried out in solvate ionic liquids and if so, how does this
compare to other ionic liquid and molecular solvents.
Herein we report the application of solvate ionic liquids as
a solvent for the rapid and high yielding synthesis of a-amino-
phosphonates in a three-component reaction. This reaction
proceeds at room temperature in 5 minutes, with the majority of
crude products being obtained by precipitation and are
analytically pure, with minimal workup.
This work began by examining the Kabachnik–Fields reac-
tion (i.e. three-component reaction) to minimize reagent
handling and as it represents the more efficient reaction
pathway compared to pre-synthesising the imine. As a model
system for optimisation, benzaldehyde 1, aniline 2, and
diphenyl phosphite were chosen (Table 1).
Entry
Solvent
Time (min)
Yielda (%)
1
2
3
4
[G3(Li)]TFSI
[G3(Li)]TFSI
[G3(Li)]TFSI
[G4(Li)]TFSI
30
5
1
82
87
78
91
5
a
Isolated yield.
Initially, the three-component reaction was stirred at room
temperature for 30 minutes in [G3(Li)]TFSI, accessing pure 3 in
a very promising yield of 82% (Table 1, entry 1). In an effort to
reduce reaction time, without sacricing the yield, the reaction
time was reduced to 5 minutes (Table 1, entry 2), giving
a excellent yield of 87%. Further reduction to 1 minute (Table 1,
entry 3) gave the desired product in a slightly depressed yield of
78%. Using this, a 5 minute reaction was considered the
optimal due to excellent yield and the reaction occurring on
a very practical timescale. Repeating this reaction in [G4(Li)]
TFSI, gave the desired product in an excellent yield of 91%
(Table 1, entry 4). Note that the isolation of these compounds
was achieved via precipitation of the crude products into water,
and not via chromatographic methods.
Nevertheless, with these conditions in hand, our attention
turned to assessing the functional group tolerance of this
reaction in SILs (Table 2). During the reaction scoping process,
many aniline derivatives were observed to react extremely
quickly, with some forming the solid product almost instantly,
preventing further stirring.
[G4(Li)]TFSI was used, a slightly diminished yield of 68% (Table
2, entry 8) was obtained. Similarly, 3-chloroaniline proceeded
well in [G3(Li)]TFSI (83%, Table 2, entry 9), a result not
consistent in [G4(Li)]TFSI (59%, Table 2, entry 10). Exploring the
effect of 3-(triuoromethyl)aniline in this reaction revealed
a excellent yields of 86% and 81% in [G3(Li)]TFSI and [G4(Li)]
TFSI, respectively (Table 2, entries 11 & 12, respectively). Intro-
ducing a bis-triuoromethylaniline derivative demonstrated the
robust nature of the reaction conditions, with both [G3(Li)]TFSI
and [G4(Li)]TFSI proceeding in good yields of 54% and 60%,
respectively (Table 2, entries 13 & 14, respectively). It is worth
noting as well that the isolation of some products from [G4(Li)]
TFSI was slightly more difficult than the [G3(Li)]TFSI, whereby
the isolated material contained traces of the glyme from the IL.
The repeated precipitation to remove these traces of glyme may
be responsible for the slightly reduced yield in certain
The rst reaction using these conditions and 4-nitroaniline
proceeded in good yield for [G3(Li)]TFSI (64%) and poor yield in
[G4(Li)]TFSI (25%) (Table 2, entries 1 & 2, respectively). The poor
yield for the latter SIL was attributed to both the poor nucleo-
philicity of the aniline and the problematic isolation of the
product, due to repeated recrystalisation. Interestingly, the
introduction of a halogen-substitution on the aniline gave
excellent yields, with both [G3(Li)]TFSI and [G4(Li)]TFSI fetching
an exemplary yields of 96% each (Table 2, entries 3 & 4,
respectively). A similar yield was obtained from the electron-
donating 4-aminophenol in [G3(Li)]TFSI (82%) and [G4(Li)]
TFSI (92%) (Table 2, entries 7 & 8, respectively). Incorporating 4-
uoroaniline into the given reaction conditions gave an excel-
lent yield in [G3(Li)]TFSI (84%, Table 2, entry 7). Though when
Table 2 Reaction scoping using substituted anilinic amines
Entry
Compound
R
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
4-NO2
4-Cl
[G3(Li)]TFSI
[G4(Li)]TFSI
[G3(Li)]TFSI
[G4(Li)]TFSI
[G3(Li)]TFSI
[G4(Li)]TFSI
[G3(Li)]TFSI
[G4(Li)]TFSI
[G3(Li)]TFSI
[G4(Li)]TFSI
[G3(Li)]TFSI
[G4(Li)]TFSI
[G3(Li)]TFSI
[G4(Li)]TFSI
64
25
96
96
82
92
84
68
83
59
86
81
54
60
4-OH
4-F
9
3-Cl
10
11
12
13
14
3-CF3
3,5-CF3
5g
a
Isolated yield.
Fig. 1 Simplified structures of solvate ionic liquids used in this work.
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Table 4 Synthesis of bis-a-aminophosphonates
instances. With this nal example of the reaction's high func-
tional group tolerance, attention was then turned to the effect of
aldehyde substitution (Table 3).
Varying the aldehyde component of the reaction, and
maintaining the aniline, scoping began with the use of 4-bro-
mobenzaldehyde, which proceeded in excellent yield of 90%
and 91% in both [G3(Li)]TFSI and [G4(Li)]TFSI (Table 3, entries 1
& 2, respectively). Utilizing p-tolualdehyde also gave encour-
aging yields of 90% in [G3(Li)]TFSI and 86% in [G4(Li)]TFSI
(Table 3, entries 3 & 4, respectively). Good yields of 69% and
59% were observed in [G3(Li)]TFSI and [G4(Li)]TFSI, respec-
tively, when using 4-nitrobenzaldehyde as the aldehyde source
(Table 3, entries 5 & 6, respectively). The reaction also proceed
well with the application of 4-uorobenzaldehyde, obtaining
the nal product in good yields of 77% and 78% in [G3(Li)]TFSI
and [G4(Li)]TFSI (Table 3, entries 7 & 8, respectively). The use of
salicylaldehyde also showed good promise, giving pure product
in 84% and 76% in [G3(Li)]TFSI and [G4(Li)]TFSI, respectively
(Table 3, entries 9 & 10, respectively) and inclusion of a bis-
substituted aldehyde (3,4-dichlorobenzaldehyde) further exem-
plied the ability of the SILs to assist this reaction, giving the
product 7f in good yields of 74% in [G3(Li)]TFSI and 79% in
[G4(Li)]TFSI (Table 3, entries 11 & 12, respectively). With this
data in hand our attention turned to the examination of
carrying out multiple reactions on bis-amines.
Entry
Compound
R
Solvent
Yielda (%)
1
2
3
4
5
6
9a
9b
9c
Ph
[G3(Li)]TFSI
[G4(Li)]TFSI
[G3(Li)]TFSI
[G4(Li)]TFSI
[G3(Li)]TFSI
[G4(Li)]TFSI
64
52
36
65
18
33
4-BrPh
4-NO2Ph
a
Isolated yield.
Repeating this process but using the ortho- and meta-
substituted diamino anilines (Scheme 2), gave varied results. As
may be expected, the formation of 11 proceeded in a good but
reduced yield in both [G3(Li)]TFSI or [G4(Li)]TFSI of 25% and
34%, respectively. This was attributed to the increased steric
hinderance imposed by the meta-substitution of the parent
diamine 10. This was consistent with our observations for the
formation of 13, possessing ortho-substitution where only 9%
was isolated for [G3(Li)]TFSI and no product was able to be
isolated when using [G4(Li)]TFSI.
A nal aspect of this work which was considered challenging
and had not been investigated previously is the synthesis of
non-symmetric bis-a-aminophosphonates, using two different
aldehydes (Scheme 3). There is a considerable challenge in this
procedure considering the speed at which the reaction takes
place, thus controlling the regiochemistry will be difficult.
Experimentally, the use of two aldehydes of similar electronic
nature were chosen, reduce any bias in the reacting system, e.g.
the use of a reactive aldehyde followed by an unreactive alde-
hyde would favour the formation of the non-symmetric product.
Therefore, in this case the rst aldehyde was added to the
solution of phosphite and amine in [G3(Li)]TFSI, then aer 5
The reactions proceeded very smoothly within 5 minutes,
giving the desired product for a range of functional groups. The
yields were variable depending on the SIL and the electronics of
the aldehyde. No discernable trend or difference was noted
between either the [G3(Li)]TFSI or [G4(Li)]TFSI, with similar
yields given for each example presented (Table 4).
Table 3 Reaction scoping using substituted benzaldehydes
Entry
Compound
R
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
4-Br
4-Me
4-NO2
4-F
[G3(Li)]TFSI
[G4(Li)]TFSI
[G3(Li)]TFSI
[G4(Li)]TFSI
[G3(Li)]TFSI
[G4(Li)]TFSI
[G3(Li)]TFSI
[G4(Li)]TFSI
[G3(Li)]TFSI
[G4(Li)]TFSI
[G3(Li)]TFSI
[G4(Li)]TFSI
90
91
90
86
69
59b
77
78
84
76
74
79
9
2-OH
3,4-Cl
10
11
12
a
b
Isolated yield.
This material possessed some of the a-
hydroxyphosphonate (17% by 1H NMR) resulting from direct attack of
the phosphite on 4-nitrobenzaldehyde.
Scheme
2 Common approaches to the synthesis of a-
aminophosphonates.
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Scheme 3 Non-symmetric bis-a-aminophosphonate synthesis.
minutes the second aldehyde was added. Using p-tolualdehyde
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procedure
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The authors would like to thank the Institute of Frontier
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