Efficient, Solvent-Free, Multicomponent Method for Organic-Base

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Efficient, solvent-free, multi-component method for organicbase-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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ACS Combinatorial Science

Efficient, solvent-free, multi-component method for organic-base-catalyzed synthesis of βphosphonomalonates 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 609-735, Republic of Korea ‡

Department of Chemistry and Chemistry institute for functional materials, Pusan National

University, Busan 609-735, Republic of Korea KEYWORDS. β-Phosphonomalonate, Multicomponent reaction, Organocatalyst, Solvent-free

ABSTRACT. The efficient, one-pot, di-n-butylamine-catalyzed, three-component synthesis of βphosphonomalonates 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 ecofriendly, alternative approach to rapid construction of a diversity-oriented library of βphosphonomalonates.

ACS Paragon Plus Environment

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INTRODUCTION The use of environmentally benign methods and reagents to minimize unwanted products, laborious work-up procedures, and evaluation of toxic gases is important in synthetic chemistry and the chemical industry. In recent years, the development of sustainable, eco-friendly 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 one-pot condensation reaction in which three or more reactants combine together to form a new compound is known as a multi-component 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 metal-free and lower activation energies. The searches for efficient, inexpensive, easily accessible, and environmentally friendly organocatalysts are still a challenge. 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 α-FPs (e.g., α-amino- and αhydroxy-phosphonates) and β-phosphonomalononitriles (β-PMNs). All these FPs are produced via P–C bond formation.10 The Michaelis–Becker and Michaelis–Arbuzov reactions (reactions of alkali- salts of dialkyl phosphonates with alkyl halides and of trialkyl phosphites (TAPs) with alkyl halides, respectively),11Pudovik reaction,12 and phospha-Michael addition10 are the main


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reactions for the synthesis of FPs. The phospha-Michael addition reaction is best for the synthesis of phosphonomalononitriles. The phospha-Michael reaction usually involves a two-pot procedure, i.e., initial synthesis of an α,β-unsaturated malonate (C–C)13in a separate step, with purification, followed by addition of a phosphorus nucleophile to the α,β-unsaturated malonate to form a P–C bond. This procedure requires a long reaction time and laborious work-up 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 phospha-Michael addition. This method is based on the in situ formation of an α,β-unsaturated malonate and subsequent reaction with a phosphorus nucleophile. There are very few reports of this type of tandem Knoevenagel–phospha-Michael reaction in the literature.14 Although phospha-Michael 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 phospha-Michael additions of dibutylphosphites (DBPs) to α,β-unsaturated malonates. In our ongoing studies to develop novel synthetic methods for various chemical transformations,15–17we

have

achieved

the

rapid

and

efficient

synthesis

of

α-

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 di-n-butylamine (DBA).19 To find these results we investigated the chemistry for the synthesis of phosphonomalononitriles using DBA as a novel organo-base catalyst. To the best of our knowledge, there are no reports in the literature of the DBA-promoted synthesis of phosphonomalononitriles. Here, we report a facile, one-pot, three-component 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 solvent-free conditions (Scheme 1).

Scheme 1. Synthesis of series of novel β-phosphonomalononitriles. RESULTS AND DISCUSSION The performance of reactions under solvent-free conditions has attracted significant attention, because such reactions are environmentally friendly and cost-effective, and have easy workup procedures, fast reaction rates, and high yields. We are interested in the development of various organic transformations under solvent-free 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– phospha-Michael reaction. For this route, it is important to choose DBA as a catalyst that gives the target β-PMN 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 base-catalyzed one-pot protocol for the synthesis of β-PMN.


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Scheme 2. Possible products formed during the one-pot synthesis of β-phosphonomalononitriles. 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 α-hydroxyphosphonates. 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 one-pot 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, 1,8-diazabicycloundec-7-ene (DBU), di-n-pentylamine, di-n-hexylamine, and DBA (Table 1, entries 9–20), which all have similar pKa values, furnished the desired phosphonomalononitriles in excellent yields, without KC and α-hydroxyphosphonates 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 two-component one-pot reaction (Scheme 3).

Scheme 3. Two-component synthesis of β-phosphonomalononitriles. 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 α-hydroxyphosphonates 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–phospha-Michael reaction, based on commercial availability, ease of handling, low toxicity, cost, and easy removal from the reaction mixture. We then compared solvent-free and solvent-based 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 solvent-free 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. Table 1.Effect of the types of catalyst on the synthesis of β-phosphonomalonatesa

Entry

catalyst

Yield (%)b

Catalyst amount (mol %)

Time (min)

PMN

KC

HPP

1

Catalyst free

-

720

nrd

2

HMTA

10

30

-

100

-

3

HMTA

10

240

20

80

-

4

HMTA

10

720

20

80

-

5

NaOH

10

300

25

75

-

6

LiOH.H2O

10

240

35

65

-

7

CS2CO3

10

360

30

70

-

8

K2CO3

10

420

20

80

-

9

Piperidine

10

15

94

-

-

10

Morpholine

10

15

92

-

-

11

Triethylamine

10

20

85

-

-

12

DBU

6

10

90

-

-

13

Di-n-pentylamine

5

12

93

-

-

14

Di-n-hexylamine

5

10

95

-

-

15

Di-n-butylamine

1

16

82

-

-

16

Di-n-butylamine

1.5

12

86

17

Di-n-butylamine

2

10

92

-

-

18

Di-n-butylamine

2.5

9

94

-

-

19

Di-n-butylamine

3

7

98

-

-


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20

Di-n-butylamine

3.5

5

98

21

ZrOCl2.SiO2

10

120c

30

-

70

22

BF3.SiO2

10

140c

25

-

65

23

Phospho sulfonic acid

10

60c

-

-

95

24

Tungstosulfonic acid

10

80c

-

-

92

a

Experimental conditions: benzaldehyde = 1 mmol, malononitrile = 1 mmol, diethylphosphite = 1 mmol, and catalyst = 3 mol% at room temperature and neat condition. b c

Isolated yields.

Reaction at 50 οC

d

No reaction

Table 2. Effects of various solvents on the synthesis of compound 4{1,1,2}a Entry

Solvent

Time (min)

Yield (%)

1

Solvent-free

4

98

2

H2O

85

50

3

EtOH

80

60

4

MeOH

90

63

5

IPA

50

72

6

PEG-400

45

85

a

Experimental 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 electron-donating groups (OMe, OEt,) were faster and gave better yields than those of aldehydes with alkyl groups (Me or


8

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i

Pr). Although halogen-substituted aldehydes gave good yields in short reaction times, the

reactions of 2-bromobenzaldehyde and 2-chlorobenzaldehyde took a long time to complete compared with the other aldehydes, because of steric hindrance by substituents at the 2-position of benzaldehyde. For reactions involving aldehydes carrying an electron-withdrawing 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 electro-negativity than nitro group. In addition the fused benzaldehydes such as anthracene-9-carabldehdye and phenanthrene-9-carabladehdye 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.


10

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Table 3. Substrate Scope of Reactiona Entry

Product

Yield (%)b

Melting Point (oC)

Found

Reported

1

4{1,1,1}

96

120-122

121-12213d

2

4{1,1,2}

98

125-127

12713d

3

4{1,1,3}

97

101-102

102-10313d

4

4{1,1,4}

94

60-62

5

4{2,1,1}

97

82-84

6

4{2,1,2}

96

75-77

7

4{2,1,3}

97

98-99

8

4{2,1,4}

95

liquid

9

4{3,1,1}

95

semisolid

10

4{3,1,2}

97

80-82

11

4{3,1,3}

98

104-106

12

4{3,1,4}

92

liquid

13

4{4,1,1}

96

108-110

14

4{4,1,2}

98

101-103

15

4{4,1,3}

98

106-108

16

4{4,1,4}

94

92-94

17

4{5,1,1}

96

108-110

18

4{5,1,2}

98

86-88

19

4{5,1,3}

98

82-84

20

4{5,1,4}

96

83-85

21

4{6,1,1}

96

95-96

22

4{6,1,2}

97

56-57

23

4{6,1,3}

98

96-98

24

4{6,1,4}

93

liquid

7713d

10213d

88-9014i

57-5814i


11


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25

4{7,1,1}

95

60-62

26

4{7,1,2}

96

71-73

27

4{7,1,3}

97

89-90

28

4{7,1,4}

93

liquid

29

4{8,1,1}

95

75-77

30

4{8,1,2}

97

60-62

31

4{8,1,3}

98

108-110

32

4{8,1,4}

94

74-76

33

4{9,1,1}

94

132-135

34

4{9,1,2}

95

149-151

35

4{9,1,3}

96

140-142

36

4{9,1,4}

91

137-139

37

4{10,1,1}

93

134-136

38

4{10,1,2}

95

144-146

39

4{10,1,3}

97

142-144

40

4{10,1,4}

92

135-137

41

4{11,1,1}

91

85-87

42

4{11,1,2}

94

90-93

43

4{12,1,1}

92

112-113

44

4{12,1,2}

93

103-105

45

4{13,1,2}

94

103-102

46

4{14,1,1}

96

96-98

47

4{14,1,2}

98

88-90

48

4{15,1,1}

95

103-105

49

4{15,1,2}

98

93-94

50

4{16,1,1}

96

101-103

51

4{16,1,2}

97

53-55

52

4{17,1,1}

95

90-91

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a

53

4{17,1,2}

96

liquid

54

4{18,1,1}

84

liquid

55

4{18,1,2}

85

liquid

56

4{19,1,1}

90

liquid

57

4{19,1,2}

91

liquid

58

4{20,1,2}

82

liquid

59

4{21,1,2}

83

liquid

60

4{1,2,2}

93c

liquid

61

4{2,2,2}

90c

liquid

62

4{3,2,2}

92c

liquid

63

4{5,2,2}

94d

liquid

64

4{6,2,2}

96 d

liquid

Experimental conditions: benzaldehyde = 1 mmol,

malononitrile = 1 mmol, diethylphosphite = 1 mmol, and catalyst = 3 mol % at room temperature and neat condition. b c

Isolated yields.

dr=70:30 (According to 1HNMR)

d

dr=58:42 (According to 1HNMR)

All the synthesized compounds were identified using infrared (IR) spectroscopy, and 1H, 13

C, and

31

P 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 1H NMR spectra, the P–CH proton 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 2bromobenzaldehyde and 2-chlorobenzaldehyde, the P–CH and CH(CN)2 proton signals appeared as multiplets at 4.53–3.72, because of steric hindrance. The anthracene-9-carabledehyde and


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Page 14 of 28

phenanthrene-9-carabaldehyde 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

13

C 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 phosphorus atom.26 The 31P 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 β-phosphonomalonates 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 β-phosphonomalonates.

Scheme 4. A plausible mechanism for β-phosphonomalonates in presence of di-n-butylamine. In summary, we developed a simple and efficient one-pot, three-component, di-nbutylamine-catalyzed 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 side-product formation, and the absence of


14

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hazardous organic solvents. This method is therefore suitable for constructing diverse libraries of phosphonomalononitriles. EXPERIMENTAL PROCEDURES 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 solvent-free 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 (2,2-dicyano-1-phenylethyl)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, – (OCH2)2], 3.57 (dd, 1J =8.0 Hz, 2J= 21.2 Hz, 1H, –P–CH), 1.67–1.17 [m, 8H, –(CH2)4], 0.89 (t, 3H, J = 7.4 Hz, –CH3), 0.80 (t, 3H, J =6.4 Hz, –CH3);

13

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 (d, J =7.5 Hz), 44.7 (d, 1JCP =143.5 Hz), 32.3, 32.1, 25.5, 18.5, 13.4;

31

P NMR (161.9 MHz,

CDCl3): δ (ppm) 19.3; FTIR (KBr): ν = 2862, 2358, 1691, 1520, 1250, 1027 cm−1. ASSOCIATED CONTENT Supporting Information. 1H NMR,

13

C NMR, and

31

P 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 *E-mail:[email protected] Notes 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. REFERENCES (1) Costa, M.; Areias, F.; Abrunhosa, L.; Venancio, A.; Proenca, F. The condensation of salicylaldehydes and malononitrile revisited: Synthesis of new dimeric chromene derivatives. J. Org. Chem.2008, 73, 1954-1962. (2) Bala, B.D.; Rajesh, S.M.; Perumal, S. An eco-friendly sequential catalyst- and solvent-free four-component stereoselective synthesis of novel 1,4-pyranonaphthoquinones. Green. Chem.2012, 14, 2484-2490. (3) Xiao, F.; Liao, Y.; Wu, M.; Deng, G.-J. One-pot synthesis of carbazoles from cyclohexanones and arylhydrazine hydrochlorides under metal-free conditions. Green. Chem.2012, 14, 3277-3280. (4) Orru, R.V.A.; de Greef, M. Recent advances in solution-phase multicomponent methodology for the synthesis of heterocyclic compounds. Synthesis, 2003, 10, 1471-1499. (5) De Graaff, C.; Ruijter, E.; Orru, R.V.A. Recent developments in asymmetric multicomponent reactions. Chem. Soc. Rev.2012, 41, 3969-4009.


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Graphical Abstract Efficient, solvent-free, multi-component method for organic-base-catalyzed synthesis of β-phosphonomalonates Reddi Mohan Naidu Kalla, Huiju Park, Hye Ri Lee, Hongsuk Suh, Il Kim


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Scheme 1. Synthesis of series of novel β-phosphonomalononitriles. 121x20mm (300 x 300 DPI)



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Scheme 2. Possible products formed during the one-pot synthesis of β-phosphonomalononitriles. 168x48mm (300 x 300 DPI)


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Scheme 3. Two-component synthesis of β-phosphonomalononitriles. 147x32mm (300 x 300 DPI)



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Scheme 4. A plausible mechanism for β-phosphonomalonates in presence of di-n-butylamine. 152x53mm (300 x 300 DPI)


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Figure 1. Reagents used to study reaction scope. 146x187mm (300 x 300 DPI)



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Image for graphical abstract 241x137mm (72 x 72 DPI)


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Efficient, Solvent-Free, Multicomponent Method for Organic-Base

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