Efficient, Solvent-Free, Multicomponent Method for Organic-Base-Catalyzed Synthesis of β-Phosphonomalonates

Article abstract of DOI:10.1021/acscombsci.5b00109

An efficient, one-pot, di-n-butylamine-catalyzed, three-component synthesis of β-phosphonomalonates has been developed. A wide range of substrates, including aromatic and fused aromatic aldehydes, were condensed with enolizable C-H activated compounds and dialkylphosphites to give the desired products in excellent yields. This method provides an eco-friendly alternative approach to rapid construction of a diversity-oriented library of β-phosphonomalonates.

Full text of DOI:10.1021/acscombsci.5b00109

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Article
Efficient, solvent-free, multi-component method for organic-
base-catalyzed synthesis of #-phosphonomalonates
Reddi Mohan Naidu Kalla, Huiju Park, Hye Ri Lee, Hongsuk Suh, and Il Kim
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.5b00109 • Publication Date (Web): 04 Oct 2015
Downloaded from http://pubs.acs.org on October 9, 2015
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Efficient, solventꢀfree, multiꢀcomponent method for
organicꢀbaseꢀcatalyzed synthesis of βꢀ
phosphonomalonates
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Reddi Mohan Naidu Kalla,† Huiju Park,† Hye Ri Lee,† Hongsuk Suh,‡ Il Kim†,*
†BK21 PLUS Center for Advanced Chemical Technology, Department of Polymer Science and
Engineering, Pusan National University, Pusan 609ꢀ735, Republic of Korea
‡
Department of Chemistry and Chemistry institute for functional materials, Pusan National
University, Busan 609ꢀ735, Republic of Korea
KEYWORDS. βꢀPhosphonomalonate, Multicomponent reaction, Organocatalyst, Solventꢀfree
ABSTRACT. The efficient, oneꢀpot, diꢀnꢀbutylamineꢀcatalyzed, threeꢀcomponent synthesis of βꢀ
phosphonomalonates has been developed. A wide range of substrates, including aromatic and
fused aromatic aldehydes, were condensed with enolizable C−H activated compounds and
dialkylphosphites to give the desired products in excellent yields. This method provides an ecoꢀ
friendly, alternative approach to rapid construction of a diversityꢀoriented library of βꢀ
phosphonomalonates.
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INTRODUCTION
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The use of environmentally benign methods and reagents to minimize unwanted products,
laborious workꢀup procedures, and evaluation of toxic gases is important in synthetic chemistry
and the chemical industry. In recent years, the development of sustainable, ecoꢀfriendly routes
for the construction of medicinally important compounds has become a significant area in the
field of synthesis.1 Reactions that can be performed in the presence of water or in the absence of
solvents are an important aspect of green chemistry.2,3 In addition, the accomplishment of
various chemical transformations in a single step is compatible with the goals of sustainable
chemistry. A oneꢀpot condensation reaction in which three or more reactants combine together to
form a new compound is known as a multiꢀcomponent reaction (MCR).4 Such reactions are
attractive because of their ability to generate two or more C–C, C–N, C–P, C–O, and C–S bonds.
In the past decade, there have been significant developments in MCRs; one of the most important
involves the use of small organic molecules as catalysts (organocatalysts).5,6 These catalysts have
advantages such as reduced toxicity, because the reactions are metalꢀfree and lower activation
energies. The searches for efficient, inexpensive, easily accessible, and environmentally friendly
organocatalysts are still a challenge.
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Functionalized phosphonates (FPs) are an important class of organophosphorus compounds,
because of their wide range of applications in materials chemistry,7 catalysis,8 and medicinal
chemistry9. There are various types of phosphonates such as αꢀFPs (e.g., αꢀaminoꢀ and αꢀ
hydroxyꢀphosphonates) and βꢀphosphonomalononitriles (βꢀPMNs). All these FPs are produced
via P–C bond formation.10 The Michaelis–Becker and Michaelis–Arbuzov reactions (reactions of
alkaliꢀ salts of dialkyl phosphonates with alkyl halides and of trialkyl phosphites (TAPs) with
alkyl halides, respectively),11Pudovik reaction,12 and phosphaꢀMichael addition10 are the main
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reactions for the synthesis of FPs. The phosphaꢀMichael addition reaction is best for the
synthesis of phosphonomalononitriles. The phosphaꢀMichael reaction usually involves a twoꢀpot
procedure, i.e., initial synthesis of an α,βꢀunsaturated malonate (C–C)13in a separate step, with
purification, followed by addition of a phosphorus nucleophile to the α,βꢀunsaturated malonate to
form a P–C bond. This procedure requires a long reaction time and laborious workꢀup
procedures, and wastes chemicals. The direct condensation of an aldehyde, malononitrile, and
phosphite (dialkyl or trialkyl), usually promoted by an acid or base, is the most convenient route
for the synthesis of phosphonomalononitriles; this is often referred to as phosphaꢀMichael
addition. This method is based on the in situ formation of an α,βꢀunsaturated malonate and
subsequent reaction with a phosphorus nucleophile. There are very few reports of this type of
tandem Knoevenagel–phosphaꢀMichael reaction in the literature.14
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Although phosphaꢀMichael addition can be performed using these methods, the majority of
existing methods have disadvantages such as long reaction times, low yields, high temperatures,
and the use of an additional energy source (microwaves) and hazardous organic solvents.
Furthermore, in most of the reported methods, the substrate is a trialkyl phosphite, and there are
few examples of the use of dialkylphosphites (DAPs).14e,j A TAP contains a trivalent phosphorus
atom and has high reactivity, but it is easily converted to a pentavalent phosphorus compound,
which changes the stability. We therefore used dialkylphosphites. There are few reports of
phosphaꢀMichael additions of dibutylphosphites (DBPs) to α,βꢀunsaturated malonates.
In our ongoing studies to develop novel synthetic methods for various chemical
transformations,15–17we have achieved the rapid and efficient synthesis of αꢀ
hydroxyphosphonates (HPPs),which have anticancer properties, using phospho sulfonic acid.18
We also synthesized chromenylphosphonates, which have anticancer properties, using the
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organic base diꢀnꢀbutylamine (DBA).19 To find these results we investigated the chemistry for
the synthesis of phosphonomalononitriles using DBA as a novel organoꢀbase catalyst. To the
best of our knowledge, there are no reports in the literature of the DBAꢀpromoted synthesis of
phosphonomalononitriles. Here, we report a facile, oneꢀpot, threeꢀcomponent process for the
synthesis of functionalized phosphonomalononitriles via the reaction of an aldehyde with
enolizable C−H activated malononitrile and a DAP in the presence of DBA at room temperature
under solventꢀfree conditions (Scheme 1).
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Scheme 1. Synthesis of series of novel βꢀphosphonomalononitriles.
RESULTS AND DISCUSSION
The performance of reactions under solventꢀfree conditions has attracted significant
attention, because such reactions are environmentally friendly and costꢀeffective, and have easy
workup procedures, fast reaction rates, and high yields. We are interested in the development of
various organic transformations under solventꢀfree conditions20–22 and in exploring the catalytic
properties of DBA in two different organic transformations.15,19 We found that DBA is a useful
precursor for selective chemical transformations. We used DBA for the tandem Knoevenagel–
phosphaꢀMichael reaction. For this route, it is important to choose DBA as a catalyst that gives
the target βꢀPMN in good yields, with total avoidance of the formation of a
Knoevenagelcondensatation (KC) product and HPPs (Scheme 2) via the Pudovik reaction.12We
therefore developed a baseꢀcatalyzed oneꢀpot protocol for the synthesis of βꢀPMN.
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Scheme 2. Possible products formed during the oneꢀpot synthesis of βꢀphosphonomalononitriles.
A model reaction between benzaldehyde, malononitrile, and diethyl phosphite (DEP) was
performed, using hexamethylenetetramine (HMTA) as the catalyst (10 mol%). After 10 min, the
reaction
mixture
contained
only
the
Knoevenagelcondensatation,
with
no
phosphonomalononitriles or αꢀhydroxyphosphonates. After 4 h, the reaction mixture contained
the Knoevenagelcondensatation and the targeted phosphonomalononitriles in a ratio of 4:1, based
on the 1H nuclear magnetic resonance (NMR) spectrum (Fig. S1, Supporting Information (SI)).
When the reaction was continued for 12 h under the same conditions, the reaction mixture
was unchanged (Table 1, entries 2–4). HPP was not formed in the presence of HMTA. These
results prompted us to test the use of other base catalysts in the oneꢀpot synthesis of PMNs. The
inorganic bases NaOH, LiOH·H2O, Cs2CO3, and K2CO3 did not proceed efficiently and only
mixtures of the KC and PMN in various ratios were obtained (Table 1, entries 5–8). In contrast,
organic bases such as piperidine, morpholine, triethylamine, 1,8ꢀdiazabicycloundecꢀ7ꢀene
(DBU), diꢀnꢀpentylamine, diꢀnꢀhexylamine, and DBA (Table 1, entries 9–20), which all have
similar pKa values, furnished the desired phosphonomalononitriles in excellent yields, without
.
KC and αꢀhydroxyphosphonates formation. The use of acid catalysts such as ZrOCl2 SiO2,
.
BF3 SiO2, phospho sulfonic acid, and tungstosulfonic acid gave mixtures of HPPs and PMNs in
various proportions (Table 1, entries 21–24) at 50 °C. Another method for
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phosphonomalononitrile synthesis involves a sequential twoꢀcomponent oneꢀpot reaction
(Scheme 3).
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Scheme 3. Twoꢀcomponent synthesis of βꢀphosphonomalononitriles.
In this method, the initial Knoevenagel condensation between benzaldehyde and
malononitrile using DBA as the catalyst gave the KC in high yield. DEP was then added in the
presence of DBA and the reaction was continued for 12h. The resultant product was identified,
using 1HNMR spectroscopy, as a 1:1 mixture of KC and PMN (Fig. S2, SI).
We used a MCR to avoid KC and αꢀhydroxyphosphonates formation in addition to the
desired phosphonomalononitriles. When the reaction was performed at room temperature in the
absence of a catalyst for 12 h, no product was observed (Table 1, entry 1). DBA was identified as
the best organic base for synthesis via the tandem Knoevenagel–phosphaꢀMichael reaction,
based on commercial availability, ease of handling, low toxicity, cost, and easy removal from the
reaction mixture.
We then compared solventꢀfree and solventꢀbased conditions (Table 2). The reaction
proceeded satisfactorily in polar solvents such as water, ethanol, methanol, isopropanol, and
poly(ethylene glycol), possibly because the reaction was completely homogeneous, but the
reaction took a long time to go to completion. The optimal molar loading of DBA was
determined by performing the model reaction using1, 1.5, 2, 2.5, 3, and 3.5 mol% of DBA under
solventꢀfree conditions at room temperature;82%, 86%, 92%, 94%, 98%, and 98% yields,
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respectively, were obtained. Increasing the amount of catalyst above 3 mol% had no effect on the
reaction. The optimal conditions are shown in Table 1, entry 19.
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Table 1.Effect of the types of catalyst on the synthesis of βꢀphosphonomalonatesa
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Yield (%)b
Catalyst amount
(mol %)
Time
(min)
Entry
catalyst
PMN
nrd
ꢀ
KC
HPP
1
2
Catalyst free
HMTA
ꢀ
10
10
10
10
10
10
10
10
10
10
6
720
30
100
80
80
75
65
70
80
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
3
HMTA
240
720
300
240
360
420
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20
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25
35
30
20
94
92
85
90
93
95
82
86
92
94
98
4
HMTA
5
NaOH
6
LiOH.H2O
7
CS2CO3
8
K2CO3
9
Piperidine
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19
Morpholine
Triethylamine
DBU
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ꢀ
20
ꢀ
10
ꢀ
Diꢀnꢀpentylamine
Diꢀnꢀhexylamine
Diꢀnꢀbutylamine
Diꢀnꢀbutylamine
Diꢀnꢀbutylamine
Diꢀnꢀbutylamine
Diꢀnꢀbutylamine
5
12
ꢀ
5
10
ꢀ
1
16
ꢀ
1.5
2
12
10
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
2.5
3
9
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Diꢀnꢀbutylamine
3.5
10
10
10
10
5
98
30
25
ꢀ
.
ZrOCl2 SiO2
120c
140c
60c
ꢀ
ꢀ
ꢀ
ꢀ
70
65
95
92
.
BF3 SiO2
Phospho sulfonic acid
Tungstosulfonic acid
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80c
ꢀ
aExperimental conditions: benzaldehyde = 1 mmol, malononitrile = 1 mmol, diethylphosphite
= 1 mmol, and catalyst = 3 mol% at room temperature and neat condition.
bIsolated yields.
cReaction at 50 οC
dNo reaction
Table 2. Effects of various solvents on the synthesis of compound 4{1,1,2}a
Entry
Solvent
Solventꢀfree
H2O
Time (min)
Yield (%)
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2
3
4
5
6
4
98
50
60
63
72
85
85
80
90
50
45
EtOH
MeOH
IPA
PEGꢀ400
aExperimental conditions: benzaldehyde = 1 mmol,
malononitrile = 1 mmol, diethylphosphite = 1 mmol,
and catalyst = 3 mol% at room temperature
The scope and limitation of this catalytic method were investigated using 21 aldehydes 1{1−21},
malononitrile 2{1}, and four DAPs 3{1−4} for library validation (Fig.1). We first examined the
reaction of benzaldehyde 1{1}, malononitrile 2{1}, and diethyl phosphite 3{2}. The data in
Table 3 show that this MCR gave the targeted phosphonomalononitriles in good yield in a short
time. The functional group on the aromatic ring of the aldehyde had a small effect on the product
yield and reaction time. The reactions involving aldehydes carrying an electronꢀdonating groups
(OMe, OEt,) were faster and gave better yields than those of aldehydes with alkyl groups (Me or
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iPr). Although halogenꢀsubstituted aldehydes gave good yields in short reaction times, the
reactions of 2ꢀbromobenzaldehyde and 2ꢀchlorobenzaldehyde took a long time to complete
compared with the other aldehydes, because of steric hindrance by substituents at the 2ꢀposition
of benzaldehyde. For reactions involving aldehydes carrying an electronꢀwithdrawing nitro
group the rate of the reaction was relatively slow and the yield of product was also low due to the
electron deficiency. The fluorine group made the rate of the reaction slower than nitro group
regardless of lower electroꢀnegativity than nitro group. In addition the fused benzaldehydes such
as anthraceneꢀ9ꢀcarabldehdye and phenanthreneꢀ9ꢀcarabladehdye readily participated in this
conversion, affording important novel PMNs in good yields (Table 3, entries 32–40).The
heterocyclic and aliphatic aldehydes also showed good reaction rate and yield of the products.
Various phosphorus nucleophiles such as DAPs, i.e., dimethyl phosphite, diethyl phosphite,
diisopropylphosphite, and dibutylphosphite, were used. In most cases, the functionalized
phosphonomalononitriles were formed in good to outstanding yields. In addition the additional
diversity of active methylene compounds such as methyl acetoacetate and ethyl benzyoylacetate
afforded pyran derivatives instead of the phosphonomalonates15.
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Figure 1. Reagents used to study reaction scope.
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Table 3. Substrate Scope of Reactiona
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4
5
6
7
Melting Point (oC)
Yield
(%)b
Entry
Product
8
9
Found
120ꢀ122
125ꢀ127
101ꢀ102
60ꢀ62
Reported
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1
2
4{1,1,1}
4{1,1,2}
4{1,1,3}
4{1,1,4}
4{2,1,1}
4{2,1,2}
4{2,1,3}
4{2,1,4}
4{3,1,1}
4{3,1,2}
4{3,1,3}
4{3,1,4}
4{4,1,1}
4{4,1,2}
4{4,1,3}
4{4,1,4}
4{5,1,1}
4{5,1,2}
4{5,1,3}
4{5,1,4}
4{6,1,1}
4{6,1,2}
4{6,1,3}
4{6,1,4}
96
98
97
94
97
96
97
95
95
97
98
92
96
98
98
94
96
98
98
96
96
97
98
93
121ꢀ12213d
12713d
3
102ꢀ10313d
4
5
82ꢀ84
6
75ꢀ77
7713d
7
98ꢀ99
8
liquid
9
semisolid
80ꢀ82
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
104ꢀ106
liquid
108ꢀ110
101ꢀ103
106ꢀ108
92ꢀ94
10213d
88ꢀ9014i
57ꢀ5814i
108ꢀ110
86ꢀ88
82ꢀ84
83ꢀ85
95ꢀ96
56ꢀ57
96ꢀ98
liquid
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4{7,1,1}
4{7,1,2}
4{7,1,3}
4{7,1,4}
4{8,1,1}
4{8,1,2}
4{8,1,3}
4{8,1,4}
4{9,1,1}
4{9,1,2}
4{9,1,3}
4{9,1,4}
4{10,1,1}
4{10,1,2}
4{10,1,3}
4{10,1,4}
4{11,1,1}
4{11,1,2}
4{12,1,1}
4{12,1,2}
4{13,1,2}
4{14,1,1}
4{14,1,2}
4{15,1,1}
4{15,1,2}
4{16,1,1}
4{16,1,2}
4{17,1,1}
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60ꢀ62
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liquid
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4{17,1,2}
4{18,1,1}
4{18,1,2}
4{19,1,1}
4{19,1,2}
4{20,1,2}
4{21,1,2}
4{1,2,2}
4{2,2,2}
4{3,2,2}
4{5,2,2}
4{6,2,2}
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93c
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94d
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aExperimental conditions: benzaldehyde = 1 mmol,
malononitrile = 1 mmol, diethylphosphite = 1 mmol,
and catalyst = 3 mol % at room temperature and neat condition.
bIsolated yields.
cdr=70:30 (According to 1HNMR)
ddr=58:42 (According to 1HNMR)
1
All the synthesized compounds were identified using infrared (IR) spectroscopy, and H,
13C, and 31P NMR spectroscopies. The IR spectra of compounds 1–59 showed the expected
absorption bands at 2389–2306, 1256–1226, and 1058–1029 cm−1, which are attributed to CN,
P=O, and P–C stretching vibrations, respectively.23In the H NMR spectra, the P–CH proton
1
signal appeared as a doublet of doublet at 3.63–3.43ppm (1J = 8.1,2J = 21.2 Hz),and another
methine peak from CH(CN)2 appeared as a triplet at 4.72–4.42 ppm (J =8.6 Hz). For 2ꢀ
bromobenzaldehyde and 2ꢀchlorobenzaldehyde, the P–CH and CH(CN)2 proton signals appeared
as multiplets at 4.53–3.72, because of steric hindrance. The anthraceneꢀ9ꢀcarabledehyde and
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phenanthreneꢀ9ꢀcarabaldehyde P–CH and CH(CN)2 proton signals appeared as multiplets, as a
result of ring strain in the fused ring systems. The remaining proton signals were observed in the
expected regions.24,25 In the 13C NMR spectra, a doublet in the region 44.8–39.5 ppm
(1Jcp=145.0–140.2 Hz) confirms the presence of a methine carbon directly attached to a
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phosphorus atom.26 The P NMR spectra of all the synthesized compounds showed a signal in
the region 23.6–17.8 ppm.
A plausible reaction mechanism for the formation of βꢀphosphonomalonates in the presence
of DBA is shown in Scheme 4. Initially the carbonyl group of aldehyde reacts with malononitrile
to form Knoevenagel product. The phosphite nucleophile is then added to the resultant
Knoevenagel product to give βꢀphosphonomalonates.
Scheme 4. A plausible mechanism for βꢀphosphonomalonates in presence of diꢀnꢀbutylamine.
In summary, we developed a simple and efficient oneꢀpot, threeꢀcomponent, diꢀnꢀ
butylamineꢀcatalyzed synthesis of functionalized phosphonomalononitriles, using easily
accessible starting materials. The most important features of this new method are a broad
substrate scope, high product yields, operational simplicity, room temperature reaction
conditions, short reaction times, the avoidance of sideꢀproduct formation, and the absence of
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hazardous organic solvents. This method is therefore suitable for constructing diverse libraries of
phosphonomalononitriles.
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EXPERIMENTAL PROCEDURES
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Typical procedure for synthesis of dimethyl (2,2-dicyano-1-phenylethyl)phosphonates
4{1,1,4}. Benzaldehyde 1{1} (1 mmol), malononitrile 2{1} (1 mmol), DBP 3{4}(1 mmol),and
DBA (3 mol%) were mixed at room temperature, under solventꢀfree conditions, with stirring.
The progress of the reaction was monitored using TLC (hexane: ethyl acetate, 6:4). When the
reaction was complete, chilled water (10 mL) was added, stirring was continued 10 min, and then
water was removed from reaction mixture. The crude product was purified by recrystallization
from ethanol to afford the desired product. The same experimental procedure was used for all the
PMNs. Detailed spectral data for all the new compounds are given below, and those for reported
compounds are given in the Supporting Information.
Dibutyl (2,2ꢀdicyanoꢀ1ꢀphenylethyl)phosphonate4{1,1,4}:1H NMR (400 MHz, CDCl3): δ
(ppm) 7.44–7.39 (m, 5H, Ar–H), 4.51 [t, J = 8.6 Hz, 1H, –CH(CN)2], 4.10–3.63 [m, 4H, –
1
2
(OCH2)2], 3.57 (dd, J =8.0 Hz, J= 21.2 Hz, 1H, –P–CH), 1.67–1.17 [m, 8H, –(CH2)4], 0.89 (t,
13
3H, J = 7.4 Hz, –CH3), 0.80 (t, 3H, J =6.4 Hz, –CH3); C NMR (100 MHz, CDCl3): δ (ppm)
130.3, 129.5, 129.3, 129.2, 111.3 (d, J= 9.7 Hz), 111.1 (d, J= 12.8 Hz), 68.0 (d, J =7.3 Hz), 67.1
1
(d, J =7.5 Hz), 44.7 (d, JCP =143.5 Hz), 32.3, 32.1, 25.5, 18.5, 13.4; 31P NMR (161.9 MHz,
CDCl3): δ (ppm) 19.3; FTIR (KBr): ν = 2862, 2358, 1691, 1520, 1250, 1027 cm−1.
ASSOCIATED CONTENT
1
Supporting Information. H NMR, 13C NMR, and 31P NMR, spectra of all synthesized
compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
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Corresponding Author
*Eꢀmail:ilkim@pusan.ac.kr
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the Fusion Research Program for Green Technologies through the
National Research Foundation of Korea, funded by the Ministry of Science, ICT and Future
Planning (2012M3C1A1054502). The authors also thank the BK21 PLUS Program for partial
financial support.
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Graphical Abstract
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Efficient, solventꢀfree, multiꢀcomponent method for organicꢀbaseꢀcatalyzed
synthesis of βꢀphosphonomalonates
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Reddi Mohan Naidu Kalla, Huiju Park, Hye Ri Lee, Hongsuk Suh, Il Kim
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Scheme 1. Synthesis of series of novel βꢀphosphonomalononitriles.
121x20mm (300 x 300 DPI)
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Scheme 2. Possible products formed during the oneꢀpot synthesis of βꢀphosphonomalononitriles.
168x48mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 25 of 28
ACS Combinatorial Science
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Scheme 3. Twoꢀcomponent synthesis of βꢀphosphonomalononitriles.
147x32mm (300 x 300 DPI)
ACS Paragon Plus Environment

ACS Combinatorial Science
Page 26 of 28
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Scheme 4. A plausible mechanism for βꢀphosphonomalonates in presence of diꢀnꢀbutylamine.
152x53mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 27 of 28
ACS Combinatorial Science
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Figure 1. Reagents used to study reaction scope.
146x187mm (300 x 300 DPI)
ACS Paragon Plus Environment

ACS Combinatorial Science
Page 28 of 28
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Image for graphical abstract
241x137mm (72 x 72 DPI)
ACS Paragon Plus Environment