l -Proline and thiourea co-catalyzed condensation of acetone

Accepted Manuscript l-Proline and thiourea co-catalyzed condensation of acetone Lin Xu, Fang Wang, Jiejun Huang, Chenggen Yang, Lei Yu, Yining Fan PII:

S0040-4020(16)30424-0

DOI:

10.1016/j.tet.2016.05.039

Reference:

TET 27766

To appear in:

Tetrahedron

Received Date: 29 April 2016 Revised Date:

11 May 2016

Accepted Date: 13 May 2016

Please cite this article as: Xu L, Wang F, Huang J, Yang C, Yu L, Fan Y, l-Proline and thiourea cocatalyzed condensation of acetone, Tetrahedron (2016), doi: 10.1016/j.tet.2016.05.039. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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L-proline and thiourea co-catalyzed condensation of acetone

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Lin Xu, Fang Wang, Jiejun Huang, Chenggen Yang Lei Yu* and Yining Fan*

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Tetrahedron journal hom epage: ww w. elsevi er.com

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L-proline and thiourea co-catalyzed condensation of acetone

Lin Xu a,b,c, Fang Wang d, Jiejun Huang b,c, Chenggen Yang,c Lei Yu a,b,c∗ and Yining Fan a,∗ a

Key Laboratory of Mesoscopic Chemistry of MOE, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093 Jiangsu Yangnong Chemical Group Co. Ltd., Yangzhou 225009, China c Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225002, People’s Republic of China d Yangzhou Polytechnology Institute, Yangzhou 225127, People’s Republic of China

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ABSTRACT

Article history: Received Received in revised form Accepted Available online

Amino acid and primary amine/amide co-catalyzed acetone condensation was investigated. It was found that L-proline had overwhelming catalytic activity over other amino acids as well as the analogues with similar structures. Surprisingly, thiourea, a very cheap and stable chemical, was found to be the favorable co-catalyst. Co-catalyzed by the recyclable L-proline and thiourea, condensation of acetone led to the useful products mesityl oxide (MO), diacetone alcohol (DAA) and isophorone (IP) in the excellent 96.3% total selectivity.

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1.

Introduction

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Keywords: Organocatalysis Acetone condensation L-Proline Thiourea Green synthesis

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Acetone is a bulk chemical that is generated as a by-product in the process of cumene oxidative cracking to produce phenol. Currently, 0.62 t of acetone is generated when producing 1 t of phenol.1 Because of the extremely higher demand of phenol than acetone, this material is largely excess in market. Thus, developing technologies that consume acetone to produce highvalue products is desirable. Among reported applications, acetone condensation is a simple but very useful organic reaction that leads to a mixture of mesityl oxide (MO), diacetone alcohol (DAA) and isophorone (IP). All of the above products can be separated by rectification in large-scale production and are useful chemicals: MO is an important intermediate in organic synthesis, pharmaceutical chemistry, agricultural chemistry, polymer and materials science2 and even in natural product syntheses;3 DAA is widely employed to prepare preservative, anti-freeze agent, extractant et. al.;4 IP is a good high boiling point solvent for lacquer and coating materials.5 Although acetone condensation is an atom-economic process that generates no waste by itself, the present technologies require strong alkaline conditions, high catalyst loading and harsh reaction conditions that generate harmful and corrosive wastes.6 Thus, developing more ecofriendly catalyst system for the reaction is of good application value.

———

2009 Elsevier Ltd. All rights reserved.

Yet, organocatalysis is an interesting research subject with both academic value and industrial application potential.7 Organocatalysts avoid the transition metal residual in product and thus are especially welcome in pharmaceutical intermediate production. Amino acids are a kind of cheap, abundant and practical organocatalysts that have been comprehensively employed in many organic reactions.8 However, because amino acids are abundant natural chiral compounds, they are always employed as cheap chiral catalysts or ligands in asymmetric synthesis while the applications to produce bulky chemicals are usually ignored.9 During our continuous investigations on green techniques,10-11 we pay much attention to amino acid-catalyzed green transformations with industrial potential.11 In 2015, we have reported the L-proline and piperazine co-catalyzed condensation of acetone to produce MO, DAA and IP.11a The solvent-free reactions led to MO, DAA and IP in 81.1% total selectivity, while 38.3% of acetone was converted.12 The catalyst L-proline could by recycled in 71.1% yield, but the co-catalyst piperazine, as a liquid dissolved in acetone, was not recoverable (Table 1, entry 1). Using polymer resin-supported catalyst poly(N-isopropylacrylamide-co-L-proline-co-piperidine) (PNLD) enhanced the catalyst recovery ratio to 85.3%, but led to decreased acetone conversion ratio (24.1%) and total product selectivity (78.7%, Teble 1, entry 2). Inorganic bases, such as NaOAc, Na2CO3, NaOH or Ca(OH)2, afforded elevated acetone

∗Corresponding author. Tel.: +86-514-87979061; fax: +86-514-87975244; e-mail: [email protected] ∗Corresponding author. Tel.: +86-25-8359462; Fax: +86-25-83317761; e-mail: [email protected]

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conversion, but were not recoverable and led to very poor total product selectivity, which was an even more important consideration factor from industrial point view (Table 1, entry 3). Recently, we tried to further improve the methodology by wide screenings of amino acids and amines/amides as catalysts and cocatalysts. It was found that L-proline had overwhelming catalytic activity over other amino acids as well as the analogues with similar structures. Surprisingly, thiourea, the very cheap and stable chemical, was unexpectedly found to be the favorable cocatalyst that obviously enhanced the total product selectivity to 96.3%. In the reaction, both L-proline and thiourea could be recycled in very high yields (Table 1, entry 4). Herein, we wish to report our findings.

1 2

C (%) a

Catalyst (mol %) L-proline (5), piperazine (2.3) PNLD

S (%) b

38.3

81.1

24.1

78.7

3

L-proline (5), Inorg. bases (2.3)f

56.8

60.5

4

L-proline (5), thiourea (2.3)

36.6

96.3

R (%) c d

11a

0

11a

95.7,d 96.3 g

This work

Highest acetone conversion. Highest total selectivity of MO, DAA and IP. c Highest catalyst recovery ratio. d Recovery ratio of L-proline. e Recovery ratio of piperazine. f NaOAc, Na2CO3, NaOH or Ca(OH)2 was employed. g Recovery ratio of thiourea.

Results and discussion

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Initially, we chose several typical amino acids with different isoelectric points as catalyst.13 After heating acetone with 5 mol % of amino acids at 90 oC for 4 h, the reaction mixtures were sent to GC analysis and the results were listed in Table 2. It was found that L-proline 2c was the only preferable catalyst for the reaction, resulting in 27.1% acetone conversion (Table 2, entry 3). Other amino acids, such as L-glusate 2a, L-cysteine 2b, Lhistidine 2d and L-arginine 2e, only led to traces of acetone conversion (Table 2, entries 1-2, 4-5). It was notable that Lcysteine 2b and L-histidine 2d that had lower or higher isoelectric point than L-proline 2c both resulted in very poor acetone conversions (Table 2, entries 2, 4). These results suggested that the acid-base property of the amino acid was not a key factor for the reaction.

Table 2 Amino acids-catalyzed acetone condensation a

Catalyst 2

Isoelectric point

C (%) b

1

L-glusate 2a

3.22

<1

2

L-cysteine 2b

5.05

<1

3

L-proline 2c

6.30

27.1

Entry

<1

a

5 g of acetone (86.21 mmol) and 4.35 mmol of amino acid were heated in a sealed tube at 90 oC for 4 h. Acetone conversion detected by GC.

b

Relationships of catalyst structures with the reaction were then investigated by using a series of amino acids with typical chemical structures (Table 3). 5-Aminopentanoic acid 2f and 2aminopentanoic acid 2g, the reductive ring-open product of Lproline 2c, resulted in the largely decreased acetone conversions (Table 3, entries 2-3 vs 1). Piperidine-2-carboxylic acid 2h, also an otho-substituted cyclic amino acid but with its ring size larger than L-proline 2c, had almost no catalytic effect for the reaction (Table 3, entry 4). Although pyrrolidine-3-carboxylic acid 2i was also a cyclic amino acid with same ring size to 2c, different substitution position of carboxyl acid obviously reduced its catalytic activity for the reaction (Table 3, entry 5). Finally a reaction using D-proline 2j as catalyst was tested and led to 26.8% acetone conversion, showing that chiral configuration of the catalyst did not affect the reaction (Table 3, entry 6).

Chemical structure

C (%) b

Entry

Catalyst 2

1

2c (L-proline)

27.1

2

2f

7.0

3

2g

<1

4

2h

<1

5

2i

5.3

6

2j (D-proline)

26.8

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b

3.8

10.76

Table 3 Acetone condensation catalyzed by molecules similar to Lproline a

71.1, 0e 85.3

a

2.

Ref

11a

7.59

L-arginine 2e

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L-histidine 2d

5

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Table 1 Comparison of the methodologies

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2

a

5 g of acetone (86.21 mmol) and 4.35 mmol of amino acid were heated in a sealed tube at 90 oC for 4 h. Acetone conversion detected by GC.

b

As shown by the above results, it was suggested that chemical structure of the catalyst was the key factor of the reaction. In organocatalysis processes, the reactions of organocatalysts with substrates first generated activated intermediates. In the catalysis processes of acetone condensation, acetone 1 first condensed with amine group of catalyst to generate the intermediate 6 (eqn. 1),11a, 14a which combined with another molecular of acetone to generate 7.14b-c Compared with chain-amino acids 2f and 2g, the structure of L-proline 2c facilitated the formation of intramolecular C-H bond that stablized the intermediate 7 (Figure 1). The cyclic piperidine-2-carboxylic acid 2h might also condense with acetone, and generated the the intermediate 8. But different from the five membered ring that was in envelope configuration, the six-membered ring of 2h exsisted as boat conformation and in intermediate 8, the distances of N to H (3.65

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28.5

70.7

8.0

2.3

81.0

3

c-C6H11NH2 10b

26.4

70.1

8.5

2.1

80.7

4

4-FC6H4NH2 10c

28.4

72.6

8.5

3.7

84.8

5

3-FC6H4NH2 10d

28.6

73.2

7.6

2.2

83.0

6

2-FC6H4NH2 10e

27.5

77.9

7.7

2.6

88.2

7

C6F5NH2 10f

31.0

70.5

11.4

3.1

85.0

8

4-MeOC6H4NH2 10g

28.2

70.8

7.1

1.6

79.5

9

3,4,5-(MeO)3C6H2NH2 10h

29.0

70.7

8.5

3.8

83.0

10

PhNHNH2 10i

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0.1

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73.3

10.2

11

PhC(O)NH2 10j

29.5

74.3

8.3

4.5

87.1

12

PhC(S)NH2 10k

33.8

78.1

10.6

2.9

91.6

13

TsNH2 10l

30.0

75.1

4.4

1.8

81.3

14

NH2C(O)NH2 10m

30.6

77.7

6.7

3.0

87.4

15

NH2C(S)NH2 10n

35.8

78.6

14.5

3.2

96.3

a

SC

Å) was much further than that in 7 (1.88 Å), as calculated by computational calculation. Thus, failing to generate the intermediate stabilized by H bond led to the low acetone conversion of the reaction catalyzed by 2h (Table 3, entry 4). Positions of carboxyl acid were also a key factor for the reaction. As shown in Figure 1, in intermediate 9 generated from pyrrolidine-3-carboxylic acid 2i, the distances of reaction sites as well as the N to H were too far to take further reaction and thus led to obviously reduced acetone conversion (Table 3, entry 5).

5 g of acetone (86.21 mmol), 4.35 mmol of L-proline 2c (5 mol %) and 1.98 mmol of co-catalyst 10 (2.3 mol %) were heated in a sealed tube at 90 oC for 4 h. b Acetone conversion detected by GC.

Based on the above experimental results as well as references, a plausible mechanism was suggested. As shown in Table 4, the thioamides were superior co-catalysts over amides (Table 4, entries 12 vs 11, 15 vs 14), probably due to the fact that thioamides were able to rearrange into the highly nucleophilic SH intermediates (eqn. 1).15 In catalysis circle, condensation of acetone with L-proline 2c initially gave the intermediate 6 (eqn. 1).14 Similarly, co-catalyst thiourea 10n reacted with another molecule of acetone to generate the intermediate 11 (eqn. 2).15 Reaction of 6 with 11 afforded the hydrogen bond-stablized ionic pair 12 (eqn. 3),11a, 16 which released the co-catalyst 10n to give the intermediate 13 (eqn. 3). Hydration of 13 led to the intramolecular hydrogen bond-stablized intermediate 14, which released the catalyst 2c and generated the product DAA 4 (eqn. 4). Dehydration of 4 provided MO 3, which reacted with another molecule of acetone to give IP 5 (eqn. 4).

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Figure 1 Chemical structure of the intermediates 7, 8 and 9 calculated with density functional theory (DFT) at B3LYP/6-31G(d) level.

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L-proline 2c was lowly soluble in acetone as well as other solvents. Thus, the reaction could not be optimized by increasing L-proline dosage. As primary amines might also react with acetone to generate the acvivate intermediate, we then tried to optimize the reaction by adding them as co-catalysts. PhNH2 10a and c-C6H11NH2 10b, as typical examples for both aromatic and aliphatic amines, were first tested, but were found to be ineffective since both of the acetone conversion and the total selectivity were not obviously improved (Table 4, entries 2-3 vs 1). Introducing electron-withdrawing groups on aryl ring, 4FC6H4NH2 10c, 3-FC6H4NH2 10d, 2-FC6H4NH2 10e and C6F5NH2 10f slightly improved the total selectivities of the reaction, but such optimizations were not worth the high cost of fluoro compounds (Table 4, entries 4-7 vs 1). Electron-enriched amines showed no obvious optimizations on both acetone conversion and total selectivity of the products (Table 4, entries 8-9 vs 1). PhNHNH2 10i slightly improved both of the acetone conversion and product selectivity (Table 4, entry 10, vs 1). Amides and thioamides were also employed as co-catalyst for the reaction. PhC(O)NH2 10j led to a mediate enhancement of the reaction selectivity and its thio-analogue PhC(S)NH2 10k resulted in a obvious increasing of the total product selectivity (Table 4, entries 11-12 vs 1). TsNH2 10l did not show any total selectivity improvement for the reaction (Table 4, entries 13 vs 1). Urea 10m and thiourea 10n were also tested (Table 4, entries 1415) and it was notable that the cheap and abundant thiourea 10n led to impressive improvements on both acetone conversion and total product selectivity of the reaction (Table 4, entry 15 vs 1).

O 6 + 11

N

H O H N HO S 12

O NH2

O

-10n

(3) N

OH 13

Table 4 Co-catalyst screenings a

Entry 1

Co-catalyst 10 -

Selectivity (%)

C (%) b

27.1

MO

DAA

IP

Total

72.2

7.3

2.2

81.7

Moreover, catalyst recycle & reuse tests were performed using a reaction magnified to 3 mol acetone scale. The experimental results were given in Table 5. After each reaction, the catalyst L-

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proline 2c and co-catalyst thiourea 10n could be recycled in more than 90% yield (Table 5, entries 1-4). After a supplement of the lost catalyst and co-catalyst, the recycled 2c and 10n were employed in next turn of reactions, giving acetone conversion in 34.5-36.6% yield while the total selectivity of the products mantained above 95%.

R1 (%)b

R2 (%)b

4.1

95.4

Acknowledgements

3.7

96.3

This work was financially supported by NNSFC (21202141), Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions, the Key Science & Technology Specific Projects of Yangzhou (YZ20122029), the Innovation Foundation of Yangzhou University (2015CXJ009), and the High-Level Talent Foundation of Yangzhou University. We thank the analysis centre of Yangzhou University for assistances.

Selectivity (%)

C (%)b

MO

DAA

IP

1

0

c

95.0

95.2

36.6

77.9

13.1

2

1

95.7

91.9

34.7

79.9

12.7

3

2

93.9

96.3

36.2

79.2

13.6

3.3

96.1

4

3

94.7

93.9

34.5

80.1

12.9

3.1

96.1

a

3.

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174 g of acetone (3 mol), 17.26 g of L-proline 2c (0.15 mol, 5 mol %) and 5.33 g of thiourea 10n (0.07 mol, 2.3 mol %) were heated in a sealed autoclave at 90 oC for 4 h. b R1 = recovery ratio of L-proline 2c; R2 = recovery ratio of thiourea 10n; C = Acetone conversion. Detailed analysis procedures of these parameters were given in ESI. c First use.

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References and notes 1.

2.

3. 4.

5. 6.

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Experimental Section

Supplementary data

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016

Conclusions

In conclusion, we investigated amino acid and primary amine/amide co-catalyzed condensation of acetone to produce the industrially important products MO, DAA and IP. It was found that L-proline had overwhelmingly superior catalytic activity over other amino acids, regardless of their isoelectric points and chemical structures. The phenomenon was suggested to be ascribed to the unique chemical structure of Lproline, which allowed the generation of the moderately stable intermediate that facilitated the reaction. A series of primary amines/amides were screened as co-catalysts and it was found that the cheap and abundant material thiourea were good cocatalyst, leading to the excellent 96.3% total product selectivity. In the reaction, more than 90% of the catalyst and co-catalyst could be recycled and reused in next turn of reaction without deactivation. More investigations on organocatalysis are ongoing in our laboratory. 4.

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Total

174 g of acetone (3 mol), 17.26 g of L-proline 2c (0.15 mol, 5 mol %) and 5.33 g of thiourea 10n (0.07 mol, 2.3 mol %) were heated in a sealed autoclave at 90 oC for 4 h and then cooled to room temperature by cold water. The precipitated catalyst & cocatalyst 2c and 10n were isolated from the reaction liquid by filtration. Evaporation of the filtrate (0.3 kpa, 120 oC) afforded another part of recycled 2c and 10n as the residue and the liquid product mixture as the fraction. The product mixture was sent to GC analysis. The recycled 2c and 10n mixtures was combined and sent to next turn of reaction after a supplement of the lost weight (Contents of 2c and 10n were determined by spectrophotography and chem-titrimetry analysis respectively, as given in ESI).

Table 5 Catalyst recycle & reuse test a

Entry

4.3 Procedures for catalyst recycle & reuse test

GC analysis of the reactions was performed by using a Shimadzu GC-2014 instrument. The detailed conditions were given in ESI. The acetone conversions and product selectivities were obtained through internal standard curves. The L-proline contents were determined by spectrophotography analysis. The thiourea contents were determined by chem-titrimetry analysis. Details of the above methods were given in ESI. Computational calculation employed density functional theory (DFT) at B3LYP/6-31G(d) level using Gaussian 09 programme.17

7.

4.2 General procedure for acetone condensation To a 15 mL pressure tube, 5 g of acetone (86.21 mmol), 4.35 mmol of L-proline 2c (5 mol %) and 1.98 mmol of co-catalyst 10 (2.3 mol %) were added. The tube was then sealed and heated at 90 oC for 4 h. The mixture was cooled to room temperature and sent to GC analysis.

8.

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