Ionic Liquids in Organic Synthesis - American Chemical Society

Chapter 14

Ionic Liquid: A Green Solvent for Organic Transformations II Downloaded by UNIV MASSACHUSETTS AMHERST on August 6, 2012 | http://pubs.acs.org Publication Date: January 18, 2007 | doi: 10.1021/bk-2007-0950.ch014

1

2

3

Shui-Ling Chen , Guan-Leong Chua , Shun-Jun Ji , and Teck-Peng Loh * 2,

1

2

Department of Chemistry, 3 Science Drive 3, National University of Singapore, 117543, Singapore Division of Chemistry and Biological Chemistry, Nanyang Technological University, 637616, Singapore College of Chemistry and Chemical Engineering, Suzhou University, Jiangsu 215006, China 3

Recently, the research into ionic liquids was blooming (1). This is mainly due to the favourable properties of ionic liquids, such as non-flammability, no measurable vapour pressure, low toxicity, reusability, low cost and high thermal stability. In addition to the polar properties of the ionic liquids, they are noncoordinating, which can avoid any undesired solvent binding in pre-transition states. Due to their unique properties, we envisage that ionic liquids will provide interesting perspectives of how green chemistry can be integrated into organic chemistry. In this article, we will continue our previous discussion and provide the details of current investigations we have done on using ionic liquids in reactions involving allylation reaction and the synthesis of bis(indolyl)methanes and polyhydroquinoline derivatives.

InCl -Promoted Allylation of Aldehydes in Ionic Liquids (2) 3

Allylation reactions of various carbonyl compounds are valuable C-C bond forming reactions for the preparation of synthetically useful homoallylic alcohols (2). Although Lewis acid or Brønsted acid catalyzed allylation reactions in aqueous media with allytributyltin have been reported (2,3,4), more active and efficient catalytic systems are still highly sought-after. Recently, our group had © 2007 American Chemical Society

In Ionic Liquids in Organic Synthesis; Malhotra, S.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.

177

178 investigated the InCl -promoted allylation reactions of aldehydes using allyltributyltin in ionic liquids. We first carried out our study on the InCl -promoted allylation using benzaldehyde and allyltributyltin in various different type of ionic liquids. The results are summarized in Table 1. It was found that the allylation reactions went smoothly with moderate to good yields (60% to 80%). Among them, [hmim]Cl and [omim]Cl gave us the best results (80% and 82% respectively). 3

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Table 1. InCl -promoted allylation of benzaldehyde in various types of ionic liquids 3

Ο

OH Η

[I

+

.^V/SnBua

j

Ionic liquid lnCI 1.2 equiv. 3

1.0 equiv.

Entry

2

1.2 equiv.

Ionic Liquid

^ N ^ N ^ ^ - ^ /

[I

3

Temp (°C)

(fo^j

Yield

40

16

70%

25

16

80%

25

14

82%

25

12

75%

55

16

68%

60

16

66%

45

14

60%

40

14

62%

[hmimJCl 3

^ N ! > ^ ^ ^ ^

[hpy]Br a

Isolated yield.


179 We then directed our studies to investigate the allylation reaction with various aldehydes in the presence of InCl in hexylmethylimidazolium chloride, [hmimJCl. The results are shown in Table 2. In all cases, InCl proved to be an efficient promoter for both aromatic and aliphatic aldehydes to afford the desired products in moderate to high yields. 3

3

Table 2. InCI -promoted allylation reaction with various aldehydes using [hmimJCl. Downloaded by UNIV MASSACHUSETTS AMHERST on August 6, 2012 | http://pubs.acs.org Publication Date: January 18, 2007 | doi: 10.1021/bk-2007-0950.ch014

3

Ο

^v/SnBu

[hmimJCl

OH

3

R^H 1.0 equiv.

1.2 equiv.

Entry

Aldehyde

lnCI 1.2 equiv. 3

1

Time (hour)

Yield

8

93%

14

88%

14

86%

16

82%

16

78%

18

76%

20

73%

20

72%

a

l

Isolated yield of allylation product. All of the products were confirmed by U NMR and C NMR spectroscopy ,3

Efforts were made to recycle and reuse the ionic liquid and catalyst. This process was investigated starting with fresh [hmimJCl and 4-chlorobenzaldehyde in the presence of InCl (Table 3). After the reaction, the ionic liquid, together 3


180 with the InCl , was recycled and reused for the second cycle. Unfortunately, no desired product was obtained (Table 3, entry 2). This could be due to the transmetallation of tin with InCl . Thus, 1 equivalent of InCl was required to be added to the recycled ionic liquid at every cycle to allow the allylation reaction to proceed in good yields (Table 3, entries 3,4 and 5). 3

3

3


Table 3. Recycling study on the allylation reaction in [hmimjCl. Ο

OH [hmim]CI lnCI 1.2 equiv.

J

3

Cl^

1.0 equiv.

1.2 equiv.

Entry

CI 3

Yield

Cycle

1 1 cycle 2 2 cycle 3 3 cycle 4 4 cycle 5 5* cycle Isolated yield of allylation product. Without addition of InCl . st

nd

b

rd

th

a

86% 0% 80% 76% 66%

b

3

We also investigated the asymmetric version of allylation reaction in ionic liquids by adding different types of chiral ligands. We screened through some of the chiral ligands, as shown in Figure 1, with 4-chlorobenzaldehyde in [hmim]Cl. Among them, (S)-2-(diphenylmethanol)-l-(2-pyridylmethyl) pyrrolidine 7 gave the best enantioselectivity.

Figure 1. Chiral ligands.


181


We then proceeded to use 7 and examined a series of ionic liquids in the asymmetric allylation reaction. The results are summarized in Table 4. The allylation proceeded smoothly in these six ionic liquids with low to moderate enantioselectivities (16% to 48% ee), and the reaction carried out in [hmimJCl gave the best result (Table 4, entry 2, 88% yield, 48% ee). The reaction of various aldehydes in [hmimJCl and 7 as the chiral ligand was subsequently studied and good to moderate yields were obtained. The results are shown in Table 5. The aromatic aldehydes gave the desired product

Table 4. Enantioselective allylation of 4-chrolobenzaldehye using (5)-2(diphenylmethanol)-l-(2-pyridylmethyl) pyrrolidine 7 in various ionic liquids. Ο

, n C ,

/ ^ Λ • II I C l " " ^ ^ 1.0 equiv.

^ S n B u

Η

3

1.2 equiv.

_

OH

3

H Ä Ionic Liquid /—\ Ph C

M

. CI

>T*Ph

N

OH

7 1.0 equiv.

Entry

Ionic Liquid N

-

v

N

v ^

b

^/qr\

Yield

ee

35

86%

39%

25

88%

48%

65

84%

16%

25

78%

40

82%

35

80%

[bmimJCl [hmim]Cl "

γ

[bmmim]Cl - N ^ N ^ ^ ^ /

[hmim]BF

26%

4

21%

[bpyJBr ® N ^ \ ^ ^ -

b

38%

* Isolated yield. The enantioselectivities were determined using HPLC analysis of the esterfrom0-methyl- (5)-mandelic acid.


182 Table 5. Enantioselective allylation of aldehyde catalyzed by (S)-2(diphenylmethanol)-l-(2-pyridylmethyl) pyrrolidine 7 in [hmim]Cl. Ο A

lnCI

3

. " 1.0 equiv.

R n

H

^ S n B u 1.2 equiv.

1 2 6 q U l V

3

[himim]CI I \ ?h

R R

OH

Ν


•

pH :

II 7 Entry

Aldehyde

1.0 equiv. 3

Yield

ee

0

1

89%

56% (Ä)

2

88%

48% (R)

3

88%

46% (R)

88%

42% (Ä)

85%

39% (Ä)

81%

10% (S)

79%

12% (R)

76%

8% (Ä)

0

4 0

5 6 ^^^^^^^^ 7 0

8 8

b

Isolated yield. The enantioselectivity was determined by *H NMR analysis of the ester from 0-methyl-(S)-mandelic acid. The absolute configuration was determined by comparing with the literature values of optical rotations (7). c

with moderate enantioselectivities (Table 5, entries 1, 2, 3, 4 and 5) while the aliphatic aldehydes gave low ee values (Table 5, entries 6, 7 and 8). In conclusion, we had explored the InCl -promoted allylation reaction in ionic liquids. The first study on the asymmetric allylation in ionic liquids was also reported. Although only moderate enantioselectivities were obtained, these results served as starting points for our future research. 3


183


Lewis Acid-Catalyzed Synthesis of Bis(indolyl)methanes in Ionic Liquids (8,9) The biologically active indoles and their derivatives have long been of interest as pharmaceuticals (10). Bisindolylalkanes and their derivatives have received more attention because of their existence as bioactive metabolites of terrestrial and marine origin (11). The simple method for the synthesis of this class of compounds involves the electrophilic substitution of indoles with various aldehydes and ketones in the presence of either protic (12) or Lewis acids (13,14). However, more than stoichiometric amounts of Lewis acids are required due to deactivation of the catalyst by the basic nitrogen (15). Recently, LiC10 (16), In(OTf) (17) and I (18) were found to catalyze this reaction. Although these catalysts are very useful and efficient, the long reaction time (4 to 10 hours), complicated manipulation, along with the use of organic solvents with their poor recovery and reusability, limited their development from the viewpoint of green chemistry. Hence, we decided to investigate the synthesis of bis(indolyl)methanes in ionic liquids catalyzed by an appropriate Lewis acid. First, we studied the effect of different ionic liquids on this reaction using In(OTf) . Six different systems using [bmim]BF , [bmim]PF , [hmim]PF , [omim]PF , [dmim]PF and [hmimJCl were employed in our investigation. The results are shown in Table 6. It was found that in BF and PF type ionic liquids, the electrophilic substitution reactions of indoles with 4-chlorobenzaldehyde proceeded smoothly with high yields. However, no desired products were obtained when using [hmimJCl (Table 6, entry 6). We then examined the catalytic activity of different Lewis acids in [omim]PF and the results are as shown in Table 7 . The reaction proceeded 4

3

2

3

4

6

6

6

6

4

6

6

Table 6. In(OTf)3-cataIyzed synthesis of 3,3'-bis(indolyl)-4chlorophenylmethane in various ionic liquids

ci Ionic Liquid 1 ml

Η

ln(OTf) 5 mol% 3

2.0 equiv.

Entry

2 3 4 5 6 a

1.0 equiv.

Ionic Liquid [bmim]PF [hmimJPF [omim]PF [dmim]PF [bmim]BF [hmimJCl 6

6

6

6

4

Time (min) 15 15 15 60 15 720

1

Yield

89% 95% 96% 82% 81% 0%

Isolated yield.


184 smoothly with all the investigated catalysts. Among them, In(OTf) showed the highest catalytic activity as the reaction was completed in 15 mins (Table 7, entry 1). We also found that when a weaker Lewis acids such as ZnCl (Table 7, entry 4) was utilized, longer reaction times were required. 3

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Table 7. Synthesis of 3,3'-bis(indolyl)-4-chlorophenylmethane using different Lewis acids in [omim]PF . Downloaded by UNIV MASSACHUSETTS AMHERST on August 6, 2012 | http://pubs.acs.org Publication Date: January 18, 2007 | doi: 10.1021/bk-2007-0950.ch014

6

CI

Η

Entry

a

1 2 3 4 5 Isolated yield.

Η

Lewis acid (mol%)ι

Time (hour)

Yield"

In(OTf) (5) BiCl (10) YbCl (5) ZnCl (10) InCl (10)

0.25 1.5 4 7 1

96% 93% 87% 79% 71%

3

3

3

2

3

The reactivities of various aldehydes were then investigated with the optimized In(OTf) in [omim]PF system. The results are shown in Table 8. Overall, the reaction proceeded with both aromatic and aliphatic aldehydes with good to excellent yields. We then continued our study on the reusability of the In(OTf) in [omim]PF . We found that the catalytic activity of In(OTf) gradually decreased in the second and third cycles (Table 10). In the fourth cycle, we did not observe any desired product. However, following the addition of another 5 mol% of In(OTf) to the recycled [omim]PF , the reaction proceeded with the same efficiency as fresh ionic liquid. Although we have developed an efficient In(OTf) -catalyzed electrophilic substitution reaction of indoles with various aldehydes to synthesize the bis(indolyl)methanes, the deactivation of In(OTf) was observed during the recycling process. As a result, it is essential for us to continue our study to develop a more practical and efficient catalytic systems. 3

6

3

6

3

3

6

3

3


Continued on next page.



186 Table 8. Continued Product Γζ/ne fmin^

Entry

Yield*

OMe

8


O

9

r

u

C

76%

20

73%

O

r^^i

ι^Ν O

8

T

15

XkJ

X Η

Η b

All products were characterized by *H NMR, IR and Η RMS spectra. Isolated yield.

Table 9. Synthesis of 3,3'-bis(indolyl)-4-chlorophenylmethane using recycled [omim]PF with In(OTf) . 6

3

CI

Η

Entry 1 2 3 4 a

Cycle 1 cycle 2 cycle 3 cycle 4 cycle st

nd

rd

th

Time (hour) 0.25 48 48 48

Η 1

Yield 96% 87% 42% 0%

Isolated yield.

Fe(III) salts are well known to catalyze many organic transformations, including oxidation of sulfides (19), Michael reaction (20), thia-Fries rearrangement (21) and the synthesis of 1,6-anhydroglucopyraboses (22). Recently, Suranna et al. reported the Michael addition of acetylacetone and methyl vinyl ketone in ionic liquids catalyzed by several metal complexes (23), including FeCl -6H 0. They found that the catalytic activity was strongly dependent on the presence of halide impurities of the ionic liquids. In view of the excellent properties of Fe(III) salts such as commercial availability, ease of handling and low toxicity, we decided to investigate the synthesis of bis(indolyl)methanes using Fe(III) salts as the catalyst. 3

2


187 We screened through a series of Fe(III) salt for the condensation reaction of indoles and 4-chlorobenzaldehyde using [omim]PF . The results are summarized in Table . We found that 96% yield was obtained while using FeCl -6H 0 as the catalyst (Table , entry 1). The activity of FeCl -6H 0 was shown to be as good as the activity of In(OTf) (Table , entry 9). Using Fe(N0 ) -9H 0 as a catalyst, the reaction proceeded slowly and, after 48 hours, 95% yield was obtained. However, when changing the catalyst to Fe (S0 ) ;cH 0, the condensation reaction did not proceed (Table , entry 3). We also tested on the catalytic activities of other different transition metal chlorides, such as CoCl -6H 0, NiCl -6H 0, CuCl -6H 0, SmCl -5H 0 and LiCl (Table , entry 4 to entry 8). Among them, only CoCl -6H 0 is able to promote the condensation reaction and give us the desired product in 55% yield (Table , entry 4). 6

3

3

2

2

3

3

2

4

3

3

2

2


2

2

2

2

2

3

2

2

2

2

Table 10. The condensation reaction of indole and 4-chlorobenzaldehyde in [omim]PF with various Lewis acids. 6

CI

Η

Entry 1 2 3 4 5 6 7 8 9 a

Lewis acid (mol%) FeCl -6H 0 (5) Fe(N0 ) -9H 0 (5) Fe (S0 ) JcH 0 (5) CoCl 6H 0 (5) NiCl -6H 0 (5) CuCl -6H 0 (5) SmCl -5H 0 (5) LiCl(10) In(OTf) (5) 3

2

2

3

3

4

3

r

2

2

2

2

2

2

2

3

2

3

Η

Yield* 96% 95% 0% 55% 0% 0% 0% 0% 96%

Time (hour) 0.5 6.5 48 48 48 48 48 48 0.25

Isolated yield.

With the above information, we continued our study on the reusability of the [omim]PF6/FeCl -6H 0 system. In Table , we compared the yields of the condensation reaction using the recycled [omim]PF with two different catalysts, In(OTf) and FeCl -6H 0, and it was found that [omim]PF6/FeCl -6H 0 can be easily recycled and reused for the condensation reaction up to at least 4 cycle with good yields. 3

2

6

3

3

2

3


2

188 Table 11. The condensation reaction using recycled [omimJPFii/IniOTf^ and [omimlPFö/FeCla-oHiO. CI

ι

j]

[omim]PF 1 ml

.

Ν Η

Lewis acid CI


2.0 equiv.

1

6

1.0 equiv.

Entry

Catalytic System

1

[omim]PF /FeCl -6H 0

2

[omimJPFö/IntOTfb

6

3

s

2

I ' cycle 96% (0.5 h) 96% (0.5 h)

Yield" (time) 2 cycle 3 cycle 91% 91% (3 h) (23 h) 87% 42% (48 h) (48 h) nd

th

4 cycle 87% (24 h) 0% (48 h)

rd

Isolated yield.

In short, we reported the first Fe(III)-catalyzed condensation reaction of indoles and aldehydes. It is noteworthy that the FeCl -H 0/[oiriim]PF catalytic system can be recycled and reused up to four cycles without any significant loss of activity. 3

2

6

Ionic Liquids-Promoted One-Pot Synthesis of Polyhydroquinoline Derivatives under Solvent Free Conditions(24) Recently, much attention has been directed towards the synthesis of 1,4dihydro pyridyl compounds. This is mainly due to their biological activities (2530). This group of compounds are known as the "chain-cutting agent" of factor IV channel (25-28) which can cure the disordered heart ratio (29,30). As a result, many methods were reported for the synthesis of these polyhydroquinoline derivatives. However, most of them require long reaction times, harsh reaction conditions and large amount of organic solvent. Therefore, simpler methods to synthesize this useful polyhydroquinoline are sought after. To continue our previous work, we developed a four-component synthesis of polyhydroquinoline derivatives in the presence of a catalytic amount of ionic liquids under solvent free condition (Scheme 1). 1


189


Scheme I. Ionic liquid-catalyzedfour-component synthesis of polyhydroquinoline derivatives in neat condition.

We screened through this reaction with various ionic liquids at 90°C. The results are shown in Table 121. We found that [hmim]BF (Table 121, entry 2) gave us the best yield in the shortest reaction time. 4

Table 12. Ionic liquid-catalyzed four-component synthesis of polyhydroquinoline derivatives in neat condition.

Entry

1 2 3 4 5 6 7 a

Ionic Liquid

[bmim]BF [hmim]BF [omim]BF [nmim]BF [dmim]BF fhmim]PF [hmim]Br

4

4

6

4 4 4

2

Time (min)

Yield

7 8 15 6 10 10 12

83% 95% 91% 86% 96% 95% 96%

Isolated yield.

Considering the reaction time and yield, [hmim]BF was selected as the optimum catalyst for this reaction (Table 121, entry 2). We then continued our study using various aldehydes with catalytic amounts of [hmim]BF . The results are summarized in Table . The reactions with both aliphatic and aromatic aldehydes went smoothly and gave the desired products in high yields (89% to 96%). 4

4


190 Table 13. [hmim]BF -catalyzed synthesis of polyhydroquinoline derivatives with various aldehydes. 4

Ο

1 mmol

Entry Downloaded by UNIV MASSACHUSETTS AMHERST on August 6, 2012 | http://pubs.acs.org Publication Date: January 18, 2007 | doi: 10.1021/bk-2007-0950.ch014

1 ^

1 mmol

NH OAc 4

Ο

1 mmol

Product

i2mol%

Time (min)

Yield*

9

/

•

Obtained

Repprted(3lf,32)

96%

260-261

263-264

10

95%

227-229

2654-226

8

95%

246-247

245-246

10

94%

235-137

210-212

5

94%

251-253

197-199

12

93%

267-268

297-298

OMe

0

1

0

V

Η

ο

2

0

Q

0

- J ' l i l i '

E

t

Η CI

o Y o

3 '

Η OH

^L^OMe

4

o

5

ο / '

6

M o

0

γ

Ν"^Η

0

I

0

J ' l i l l *

0

0


191 Table 13. Continued. Obtained

Reported(31f,32)


208-210

248-250

242-244

153-154

a

Isolated yield.

In short, we have developed an efficient [hmim]BF -catalyzed fourcomponent condensation reaction of dimedone with various aldehydes, ammonium acetate and ethyl acetoacetate to form polyhydroquinoline in high yields. 4

Conclusion In addition to our previous investigations on ionic liquids, our group has effectively developed useful methodologies for allylation reactions. We have also investigated the synthesis of bis(indolyl)methanes and polyhydroquinoline derivatives using ionic liquids. We strongly believe that the simplicities of all these methods have provided easy access and effective pathways to synthesize synthetically useful organic compounds. In conclusion, we envisage that the use of ionic liquids will continue to attract attention in years to come.


192

Acknowledgement We thank the Nanyang Technological University and the National University of Singapore for their generous financial support. We would also like to acknowledge the hard work, perseverance, and insight of the graduate students that made this review possible.


References 1. 2. 3. 4.

5. 6. 7. 8. 9. 10. 11.

12. 13.

14.

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Ionic Liquids in Organic Synthesis - American Chemical Society

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