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Phosphorus, Sulfur, and Silicon and the RelatedElementsPublication details, including instructions for authors and subscription information:http://www.tandfonline.com/loi/gpss20

Microwave-assisted synthesis of β-thiodiketonecompounds by multicomponent reactionXiangmei Maab, Mingxu Zhangb & Bin Wanga

a Institute of Chemical Engineering, Anhui University of Science & Technology, Huainan,Anhui 232001, P.R. China.b Institute of Earth & Environment, Anhui University of Science & Technology, Huainan,Anhui 232001, P.R. China.Accepted author version posted online: 30 Oct 2014.

To cite this article: Xiangmei Ma, Mingxu Zhang & Bin Wang (2014): Microwave-assisted synthesis of β-thiodiketonecompounds by multicomponent reaction, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:10.1080/10426507.2014.974091

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Microwave-assisted synthesis of β-thiodiketone compounds by multicomponent reaction

Xiangmei Ma a,b

, Mingxu Zhang b and

Bin Wang

a,*

aInstitute of Chemical Engineering, Anhui University of Science & Technology, Huainan,

Anhui 232001, P.R. China.

bInstitute of Earth & Environment, Anhui University of Science & Technology, Huainan,

Anhui 232001, P.R. China.

Abstract : An efficient synthesis of β-thiodiketone derivatives using ammonium acetate as a

catalyst, from mercaptans, aldehydes and acetylacetone in an aqueous medium under the

irradiation of microwave is described. Compared with the conventional refluxing conditions,

the present method showed the advantages of simple work-up and shorter reaction times.

R1SH + + R2CHO

R1S R2

O

CH3

O

MWC

O

CH3CH3 C

O

CH2CH3

ammonium acetate

water

Keywords : Microwave irradiation, multicomponent reaction, β-thiodiketone.

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Introduction

Multicomponent reaction (MCR) constitute an especially attractive synthetic method to

generate molecular diversity. In these reactions, three or more easily accessible reactants

were combined in a single chemical step to produce products. In contrast to the multistep

synthesis, MCRs avoid time-consuming tasks and costly purification processes. In addition,

many reactions with water as solvent are environmentally safe and economical [1]

. In 1850, a

MCR was first reported as a fascinating tool in organic synthesis [2]

, and quickly gained

attention

a s one that offered selectivity with high atom economy, and simplistic operation. It

has been extensively applied by synthetic chemists as an effective method to generate

molecular

*Address correspondence to Wang Bin, Department of Chemical Engineering, Anhui

University of Science and Technology, Huainan, Anhui, 232001, China. E-mail:

wbmxmwzc@126.com.

diversity in recent years [3]

.

Organosulfur compounds are key skeletons in pharmaceutical chemistry and crucial

intermediates in synthetic organic chemistry [4-6]

. New approaches have been developed to

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synthesize diverse drugs which are increasingly in demand in medicinal chemistry [7]

.

β-thiodiketone derivatives are a type of functionally active components which have HIV

protease inhibitory activity and significant diuretic function. They also have the effect of

antibacterial, antiviral and higher application values in pharmacognosy and pharmaceut ical

chemistry[8-10]

. Therefore, the discovery of mild and practical routes for the synthesis of

β-thiodiketone derivatives continues to attract the attention of researchers.

The development of resource and eco-friendly process has become a focal point of

chemical research in recent years [11]

. Microwave–assisted organic synthesis is a highly

useful tool in organic synthesis for improving reaction yield and reducing thermal

degradation [12-14]

. Therefore, many research groups are adopting microwave in organic

synthesis as a ―green‖ technology [15-16]

. Herein，we wish to describe a more simple protocol

for a environment-friendly, rapid, and convenient synthesis of β-thiodiketone derivatives

through a one-pot three component condensation reaction.

Results and Discussions

β-thiodiketone derivatives can be prepared from the corresponding mercaptans,

aldehydes and acetylacetone in aqueous solutions under thermal condition[17]

. But the

process took a long time to complete. We decided to explore a simple and efficient method

for the synthesis of β-thiodiketone using microwave. In search for an optimization of reaction

conditions, the one-pot reaction for the three components of n-laurylmercaptan with

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benzaldehyde and acetylacetone as model reaction was studied and the results are

summarized in Tables1-3. To date, it has been synthesized in a maximum of 72 % yield with

a reaction time of 12 h under refluxing conditions. We optimized the microwave power,

reaction time and the ratios of reactants in the said model reaction. Through these

experiments, at 195 W, a time of 40 min, 2:1:1 ratios of acetylacetone, mercaptan, and

aldehyde were the optimal conditions to complete the reaction. Under these conditions, the

other reactions proceeded well and afforded the desired products in good to excellent yields

except 1-naphthalene formaldehyde (Table 4).This could be because of reaction

ability markedly decreases with the increase of the steric hindrance.β-thiodiketone

derivatives was obtained as shown in Table 3.

The FT-IR, 1H NMR,

13C NMR spectra and elemental analysis confirmed the structure

of the β-thiodiketone compounds. The carbonyl stretching vibration and ester (from 1689to

1699 cm-1) of the as synthesized samples are clearly seen in the IR spectrum. Carbon-

sulfurbonds (C-S) also have some related vibrations in the range from 693 to 699 cm-1

. The

13C NMR

spectrum exhibited characteristic carbonyl at 201.3 – 202.7 ppm. 1H NMR and elemental

analyses data further confirmed the product formation.

On the basis of our experimental results and by referring to the literature, the

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possible mechanism of the reaction is shown in Scheme 1. (Take benzaldehyde for example).

Firstly, acetylacetone can convert into its tautomers of enol and ketone. The catalyst might

assist in improving reactivity of aldehyde group and addition reaction to form

intermediate I. The second step, the intermediate product of II was prepared by

dehydration reaction under heating conditions, which then yields intermediate III by forming

a hydrogen bond withmercaptan. Meanwhile, the double bond of carbon is

the nucleophilic reaction site. Thus,intermediate IV could be prepared by intramolecular

addition reaction, followedby the dehydration and proton transfer to produce the final

products. This methodology is

simple,

practical route to obtain β-thiodiketone derivatives by microwave irradiation. It is much more

efficient due to short reaction times and easy work up.

Experimental

Materials

Laurylmercaptan was purchased from Aladin of analytical grade and used without

further purification in the experiment. The other chemicals and reagents were obtained from

Fuyuchemical Co., LTD ( Tianjin China ) and were used without further purification.

LWMC-201-type microwave reactor with a fixed-frequency of 2.45 GHz.

Linjiangcorporation of Science and Technology (Nanjin China ).

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The identification of the purity was checked by thin layer chromatography (TLC), which

was performed on silica gel (60–120 mesh). Iodine vapors and UV light were used for

detection.

FT-IR spectra were recorded on a Perkin Elmer FT–IR 550 spectrophotometer using

KBr

pellets and absorbencies are reported in cm−1

. 1H NMR and

13C NMR spectra were recorded on

Bruker 400 MHz spectrometer (Bruker Corporation Ltd., Germany ) using CDCl3 as a

solvent and TMS as an internal standard. Chemical shifts (δ) are given in ppm and coupling

constants (J) are reported in hertz (Hz). Spin multiplicities are given as s (singlet), d

(doublet), t (triplet) and m (multiplet). Elemental analyses were performed on a Carlo-Erba

model EA1108 analytical unit (Triad Scientific Ltd., USA ).

Synthesis and Characterizations

In the model reaction, ammonium acetate (20 mol %) as an efficient catalyst was added

to the mixture of acetylacetone (20 mmol), benzaldehyde (10 mmol), laurylmercaptan (10

mmol) and deionized water (40 mL) in a round-bottomed flask. The mixture was heated at

microwave oven with stirring for appropriate time until reaction complete. After cooling, the

reaction mixture was washed with ethylacetate (3 ×5mL). The organic layer was separated

and dried over anhydrous sodium sulfate. After evaporation of the solvent, the pure product is

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prepared by recrystallization with ethanol (Table 4). All of compounds were characterized by

spectroscopic methods.

3-[(dodecylthio）(propyl) methyl)] pentane-2,4-dione

S

O O

IR ( KBr ) ：ν = 2922 (aliphatic CH stretch), 2852 (CH2), 1699（C=O)，1463(CH)，

1355(CH3), 720[(CH2)n], 697(C-S）[18].

1H NMR ( 400 MHz, CDCl3 ) δ：3.85 (d, J = 11.1 Hz, 1H, CH ), 3.28–3.21 (m, 1H,

CH), 2.51–2.39 (m, 2H, CH2), 2.20 (s, 3H, CH3 ), 2.16 (s, 3H, CH3 ), 1.63–1.42 (m, 4H,

CH2CH2 ), 1.4–1.09 [ m, 20H, (CH2)10 ], 0.92–0.75 (m, 6H, 2CH3 ).

13 C NMR (101 MHz, CDCl3,TMS ) : δ 202.7（C=O）, 202.2（C=O）, 74.4（CH）, 44.5

（CH）, [35.1, 31.9, 30.8, 29.9，29.7，29.6，29.6，29.5，29.4，29.4，29.30，29.1, 28.9

（CH2）], 22.6（CH3）, 19.5（CH3）, 14.0（CH3）, 13.7（CH3）. Anal Calcd for C21H40SO2

：C, 70.73 ; H, 11.31; S, 8.99. Found: C, 70.25; H, 11.70; S, 8.39.

3-[( dodecylthio）(phenyl) methyl)] pentane-2,4-dione

S

O O

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IR ( KBr )：ν = 2950（C-H）, 2847 (CH2), 1691（C=O ester）, 1460 (CH), 1355 (CH3),

776 (Ph-), 718[(CH2)n], 699（C-S）.

1H NMR ( 400 MHz, CDCl3 ) δ : 7.44–7.02 ( m, 5H, C6H5 ), 4.41 (d, J = 12.1 Hz, 1H,

CH ),

4.20 ( d, J =12.1 Hz, 1H, CH ), 2.30 ( d, J =12.5 Hz, 3H, CH3 ), 2.30–2.13 (m, 2H, CH2 ), 1.83 (s,

3H, CH3 ), 1.72– 1.00 [( m, 20H, (CH2)10 ], 0.83 ( t, J = 6.5 Hz, 3H, CH3 ).

13 C NMR (101 MHz, CDCl3, TMS ) ：δ( ppm) 201.4（C=O），201.3（C=O）, [139.3,

128.7, 128.1, 127.7（C6H5-）], 74.5（CH）, 48.3（CH）, [31.9, 31.1, 30.0, 29.6, 29.2, 29.4,

29.4，29.32，29.2, 29.0, 28.9（CH2）], 28.7（CH3），22.7（CH3）, 14.1（CH3）. Anal Calcd

for C24H38SO2 ：C, 73.80 ; H, 9.81; S, 8.21. Found: C, 73.16; H, 9.87; S, 8.46.

3-[( p-toluene thiol）(phenyl) methyl)] pentane-2,4-dione

CH3

O O

S

IR ( KBr ) ：ν = 3403（C-H）, 1691（C=O ester）, 1351(CH3), 801 (Ph-), 697（C-S

）.

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1H NMR (400 MHz, CDCl3) δ :7.31 – 6.88 (m, 9H，C6H5, C6H4 ), 4.70 (d, J = 12.2 Hz,

1H，CH), 4.35 (d, J = 12.2 Hz, 1H,CH), 2.38 (s, 3H, CH3), 2.27 (s, 3H, CH3), 1.85 (s, 3H,

C H 3 ) .

13 C NMR (101 MHz, CDCl3, TMS ): δ ( ppm ) 201.3 (d, J = 14.9 Hz, 2C=O), [139.1 (s),

138.7 (s), 134.6 (s), 129.6 (s), 128.5 (d, J = 3.7 Hz), 128.1 (s), 127.7 (s),（C6H5-） ], 7

4.1 (s, CH), 52.9 (s,CH), 29.5 (d, J = 4.0 Hz, 2CH3), 21.2 (s, CH3).

Anal Calcd for C19H20SO2 ：C, 73.04 ; H, 6.45; S, 10.26. Found: C, 72.11; H, 6.37; S,

10.02.

3-[( benzylthio）(phenyl) methyl)] pentane-2,4-dione

O O

S

IR ( KBr ) ：ν = 2932（C-H）, 2907 (CH3), 1717（C=O）, 1689（C=O ester）, 1489 (CH),

1354 (CH3), 1184, 1143, 967, 853, 778(Ph-), 719 [(CH2)n], 693（C-S）.

1H NMR (400 MHz, CDCl3) δ : 7.38–7.05 ( m, 10H, 2C6H5 ), 4.26 (d, J = 12.2 Hz, 1H,

CH), 4.16 (d, J = 12.2 Hz, 1H, CH ), 3.49 (d, J = 13.6 Hz, 1H, CH2), 3.33 (d, J = 13.6 Hz, 1H

,CH2), 2.10 (s, 3H,CH3), 1.78 (s, 3H, CH3).

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13 C NMR (101 MHz, CDCl3, TMS ): δ( ppm ) 201.3（C=O）, [138.9, 137.2, 129.0,

128.7, 128.5,128.4, 127.9, 127.3（Ph-）], 74.6（CH）, 47.6（CH）, 35.2（CH2）, 30.3（

CH3）, 28.1（CH3）.

Conclusions

This work reports a new and effective method for the synthesis of β-thiodiketone

derivatives from acetylacetone, mercaptan, and aldehyde, which is more economic and

more environmentally friendly than previous methods. The method offers several advantages

such as high yield, short reaction time, simple work up, and does not require column

purification. These conditions may be ideally suited for an effective synthesis on a larger

scale.

Acknowledgments

This work was supported by the National Basic Research Program of China under Grant

973 Program（Grant No.2012CB214900）.

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2. Strecker, A. Justus Liebigs Ann. Chem. 1850, 75, 27-45.

3. Abbas, A.; Esmaeili, R. H. & Maryam, R. Phosphorus Sulfur Silicon Relat. Elem., 2011,

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4. Alves, D.; Lara, R.G.; Contreira, M.E.; Radatz, E. S.;Duarte, L.F.B.; Perin, G. Tetrahedron

Lett. 2012, 53, 3364-3368.

5. Zhang, L.; Chou, C. P.; Moo-Young, M. Biotechnol. Adv. 2011, 29, 923-929.

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4619-4628.

7. Liu, J.; Hou, S.L.; Xu, J.X. Phosphorus Sulfur Silicon Relat. Elem., 2011, 186, 2377-2391.

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2009, 6, 130-133.

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12. Jelem, R. José, S. and Simón , E. L´. O. Phosphorus Sulfur Silicon Relat. Elem., 2011, 86,

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13. Abhijit R. K. and Ganesh, A.T. Tetrahedron Lett , 2013, 54, 6592 - 6595.

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17. Li, L. Ph. D. Dissertation. Zhejiang University , China. 2011.

18. Shen, Y. F.; Sun, T. H.; Jia, J. P. Fuel. 2012, 96, 250 - 256.

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CHO

+ NH4+

C

OH

H

+

C

O

CH3CH3 C

O

CH2 C

O

CH3CH3 CHC

OH

C

O

CH3CH3 CHC

O

OAc

C

OH

HO

O

NH4+

O

O

H

O H

CH

NH4+

RSH

O

OC

SR

+

SR

OH+

O

H

O H

CH

H

+

H2O

H2O

CH3 C

O

C C

CH3

O

C

S

H

H

H

OH

+AcO-

H2O

H+

H

H

I II

R

+

-

II I IV

CHO

OCH

OH

H

Scheme 1. Plausible reaction pathway in the synthesis of β-thiodiketone

Table 1: Influence of the microwave power

Entry microwave power (W) Yield (%)

1

2

3

4

195

260

325

390

53

58

57

54

Reaction conditions: acetylacetone (10mmol), benzaldehyde (10 mmol), laurylmercaptan

(10 mmol),catalyst (20 mol%)，reaction time：60 min。

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Table 2: Influence of the microwave radiation time

Entry microwave radiation time/min Yield /%

1

2

3

4

5

50

60

70

80

90

41

53

63

64

64

Reaction conditions: acetylacetone (10mmol), benzaldehyde (10 mmol), laurylmercaptan (10

mmol), catalyst (20 mol%)，microwave power (W)：195.

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Table 3: Influence of the ratios of reactants

Entry ratios of reactants Yield (%)

1

2

3

4

5

6

1:1:1

1:1:2

1:2:1

1:2:2

2:1:2

2:1:1

64

65

67

69

71

72

Reaction conditions: catalyst (20 mol%)，microwave power (W)：195. ratios of reactants :n

acetylacetone : n benzaldehyde : n laurylmercaptan，reaction time：80 min。

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Table .4: Microwave - assisted synthesis of β-thio diketone under optimized conditions

R1SH

O O

+ + R2CHO R1S R2

O O

MW

Compounds R1 R2 Yield (%)

A1 n-C12H25— Ph— 72 %

A2 n-C12H25— CH3CH2CH2— 79 %

B1 CH3

64 %

C1 CH2

66 %

C2 n-C12H25—

ND

ND-not detected.

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