aza-Michael addition of amines to chalcones through in situ generation of Michael acceptors under neat conditions

Journal Pre-proofs Graphene Oxide as a catalyst for one-pot sequential aldol coupling/aza-Michael addition of amines to chalcones through in situ generation of Michael acceptors under neat conditions Dariush Khalili, Salime Lavian, Mohammadesmaeil Moayyed PII: DOI: Reference:

S0040-4039(19)31269-9 https://doi.org/10.1016/j.tetlet.2019.151470 TETL 151470

To appear in:

Tetrahedron Letters

Received Date: Revised Date: Accepted Date:

7 September 2019 23 November 2019 29 November 2019

Please cite this article as: Khalili, D., Lavian, S., Moayyed, M., Graphene Oxide as a catalyst for one-pot sequential aldol coupling/aza-Michael addition of amines to chalcones through in situ generation of Michael acceptors under neat conditions, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151470

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© 2019 Published by Elsevier Ltd.

Graphene Oxide as a catalyst for one-pot sequential aldol coupling/aza-Michael addition of amines to chalcones through in situ generation of Michael acceptors under neat conditions Dariush Khalili, *a Salime Laviana and Mohammadesmaeil Moayyeda Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71467-13565, Iran. E-mail: [email protected]

Abstract Graphene oxide (GO) in conjunction with tetra n-butyl ammonium bromide (TBAB) was found to function as an efficient catalyst for one-pot sequential aldol coupling/aza-Michael addition of amines to chalcones in a single reaction vessel. Benzaldehydes and acetophenone were coupled in situ to produce their corresponding chalcones which underwent a subsequent aza-Michael addition under solvent-free condition. This procedure avoids the use of precious metals and the heterogeneous nature of the GO

simplifies purification and isolation of the products by simple filtration of the catalyst.

Keywords: aza-Michael addition, chalcones, graphene oxide, solvent-free

Both academic and industrial chemistry are currently seeking new practical methods which facilitate the construction of the C-N bond mainly due to the high prevalence of nitrogencontaining compounds in pharmaceuticals and natural products.1 The conjugate addition of nitrogen-based nucleophiles to α,β-unsaturated olefins which is termed as aza-Michael reaction, is one of the most effective synthetic tools for constructing a new C-N bond.2 In this regard, βaminocarbonyl compounds, as a major product of aza-Michael reaction, have received great attention from the scientific community due to their promising properties and applications.3-7 To date, much efforts have been put forth for introducing efficient strategies for the synthesis of βaminocarbonyl compounds.8-14 Among various Michael acceptors, chalcones as biologically active scaffolds

15,

have been widely used in organic synthesis to establish Michael adducts.

However, synthesis of chalcones, as a key component in aza-Michael reaction, has still remained a great challenge because their formation needs to be carried out under strongly

acidic or basic conditions.15 Moreover, the addition of nitrogen-based nucleophiles to chalcones also has some drawbacks such as the use of toxic solvents and metals, poor compatibility with various substrate functional groups and polymerization of labile enones in acidic/basic conditions.10,

16, 17

To remove these obstacles, the use of heterogeneous catalytic systems

appears to be a valuable solution and carbon materials with superior physicochemical properties can be good nominee for this goal. Graphene oxide (GO)20, 21 as an oxide-functionalized

18, 19

derivative of graphene, is particularly promising due to the high biocompatibility and it’s rich surface chemistry and acidic nature.22,

23

Recently, in a pioneering effort, Bielawski et al.

reported a metal-free, GO-mediated, formation of chalcones in an auto-tandem fashion.24 Inspired by this report and our ongoing interests in GO-catalyzed organic reactions

25-27

we tried

the GO-catalyzed sequential aldol coupling/aza-Michael addition of amines to chalcones that generated in situ from acetophenones and benzaldehydes under solvent and metal-free conditions. The success of GO as a much greener carbocatalyst attributes to the advantages of its rich surface chemistry and its capacity to perform organic transformations in a metal-free environment, under mild reaction conditions. In this strategy, the sequential reactions also occur without separation of Michael acceptors as intermediates and a broad range of aromatic amines can be converted to the desired β-amino ketones in isolated yields of up to >94%. In fact, the present catalytic system is based on in situ production of chalcones which are commonly considered as less active substrates than other Michael acceptors in such transformations. Literature methods available for the successful addition of arylamines to electron-deficient alkenes are not simple; Michael acceptor should contain a very active double bond such as ethenetricarboxylates28 and nitroalkenes,29 and specific reaction conditions such as highly polar protic solvents,30 basic ionic liquids31 and surfactants32 are required. Even in these conditions, the efficiency of nucleophilic addition of aryl amines is not acceptable. By considering these facts, the possibility of using of aromatic amines which are weak nucleophiles in aza-Michael addition, is another attractive feature of our method. O Ar

H Carbon-based catalyst Coupling reaction

+ O H 3C

Ar

Ar

O Ar

Ar

Carbon-based catalyst, ArNH2 aza-Michael addition

Ar

NH O Ar

Graphite oxide was synthesized from natural flake graphite (particle size: <50μm, from Merck) by a modified Hummers method.33 The prepared graphite oxide was dialyzed in a dialysis bag for 48 h to ensure the complete removal of salts, residual acids and metallic impurities. Then the graphite oxide aqueous suspension was ultrasonicated for at least 1 h to form graphene oxide (GO). The as-synthesized GO was characterized completely by using various analytical techniques such as Raman, IR, XRD, UV-Vis and TGA techniques to establish its authenticity. To determine the amounts of -COOH and -OH groups, a solid-based titrimetry method was used.34 Based on the titration curves the amounts of -COOH and -OH were evaluated to be 0.71 and 1.13 mmol/g, respectively. The initial pH value of GO was 4.4, at approximately 0.1 mg mL1,

which is consistent with previous reports.35

Initially, the reaction between benzaldehyde 1a (1 mmol) and acetophenone 2a (1 mmol) was chosen as a model reaction. As a mixture of 1a and 2a was stirred in refluxing H2O, the coupling reaction was carried out in the presence of GO (80 mg) to produce the chalcone. Further reaction of chalcone intermediate with aniline (1.1 mmol) in the same condition, generated the final corresponding aza-Michael adduct 3a in very low yield (entry 1). Table 1. Optimization of the reaction conditionsa O

Ph

O H

1a

O

1) Catalyst (mg), solvent, T °C 2) PhNH2, condition

H 3C

+

NH

3a

2a

Entry

Catalyst (loading)

Solvent (condition)

Time (h)

Yield of 3ab

1

GO(80 mg)

H2O, reflux

24

12

2

GO(80 mg)

CH2Cl2, reflux

24

31

3

GO(80 mg)

THF, reflux

24

45

4

GO(80 mg)

EtOH, reflux

24

52

5

GO(80 mg)

CH3CN, reflux

24

59

6

GO(80 mg)

Solvent-free, 100 ºC

16

72

7c,d

GO(80 mg)

Solvent-free, 100 ºC

16

84

8e

GO(80 mg)

Solvent-free, 100 ºC

16

74

9f

-

Solvent-free, 100 ºC

48

trace

10c

GO(80 mg)

Solvent-free, 80 ºC

24

66

11c

GO(80 mg)

Solvent-free, 110 ºC

16

84

12c

GO(70 mg)

Solvent-free, 100 ºC

16

74

13c

GO(100 mg)

Solvent-free, 100 ºC

16

87

14c

Graphite(80 mg)

Solvent-free, 100 ºC

16

trace

15c

activated carbon (80 mg)

Solvent-free, 100 ºC

16

30

16c

r-GO (80 mg)

Solvent-free, 100 ºC

16

38

aThe

reactions were performed with benzaldehyde (1 mmol), acetophenone (1 mmol), aniline (1.1 mmol) and a carbon catalyst (type indicated). bIsolated yield. cTBAB (30 mol%) was used as an additive. dBold values reflect the best optimized condition. eReaction was performed in the presence of 20 mol% of TBAB. fBlank experiment without graphene oxide.

When other solvents such as CH2Cl2, THF, EtOH and CH3CN were applied instead of H2O (entries 2-5), maximum yield of 59% was obtained in 24 h. When the model reaction was performed under solvent-free condition at 100 °C, aza-Michael addition proceeded smoothly and the product 1,3-diphenyl-3-(N-phenylamino)-1-propanone (3a) was obtained in 72% yield within 16 h (entry 6). To our delight, when the above reaction carried out using tetra n-butyl ammonium bromide (TBAB, 30 mol%) as an additive at 100°C, the reaction was completed within 16 h and 3a was obtained in 84% yield (entry 7). The same reaction was repeated using lower loading of TBAB (20 mol%) and the product 3a was obtained in 74% yield after 16 h (Table 1, entry 8). Other quaternary ammonium salts such as TBAC and TBAI were also tested. The studies showed that TBAB and TBAC were nearly equally efficient additives for sequential aldol coupling/aza-Michael addition reaction while TBAI was found to be less effective in the model reaction. This can be justified by considering their melting points (TBAC: 41-44 °C; TBAB: 100-102 °C; TBAI: 143-146 °C) and the reaction temperature (100 °C). However, since the TBAB is more inexpensive than TBAC, this compound was chosen as the additive of choice in this reaction. Using solvent-free conditions, approaching reactants which were soluble in organic solvents and GO which was well-dispersible in H2O36 was an issue. To overcome this, quaternary ammonium salts were used where the both reactants and the catalyst experienced an efficient reaction medium to move toward each other with help of quaternary ammonium salts. So, its positive effect might be explained from the fact that TBAB can facilitate the approach of substrates to the GO surface24 and easier formation of intermediates.37 The model reaction without GO gave trace amounts of product 3a even after 48 h which confirmed the active role of the catalyst (entry 9). Lowering the reaction temperature to 80 °C decreased the yield of 3a to 66% even with a prolonged reaction time (entry 10). Moreover, an increase in the reaction temperature (110 °C) did not show any beneficial effect (entry 11). We next examined the effect of the amount of catalyst on this sequential reaction. When the amount of the catalyst was reduced to 70 mg, the yield of 3a decreased obviously while an increase in the amount of GO (100 mg) led to no increment in the yield (entries 12 and 13). Under the same conditions,

the other carbon materials like natural flake graphite, activated carbon,38 hydrazine reduced graphene oxide21 resulted in poorer yields (entries 14-16). After optimizing the conditions for both coupling and aza-Michael addition reaction, the catalytic efficiency of GO was further explored with aldehydes and anilines bearing electron donating and electron withdrawing groups (Table 2). Table 2. GO-catalyzed sequential aldol coupling/aza-Michael addition of amines to chalcones.a Ar

+

H 1

Entry

Ar'

O

O

1) GO, TBAB, solvent-free, 100 °C 2) Ar'NH2

H 3C 2a

Aldehyde

1

NH

O

Ar 3a-o

Amine

β-amino ketones NH O

H 2N

Yield (%)b

3a

84

3b

87

3c

88

NH O

3d

85

NH O

3e

90

3f

87

H3CO

H 2N

2

OCH3

NH O

EtO

3

H 2N

NH O

OEt

O

CH3

H

4

5

6

H 2N

H 2N

H 2N

CH3

H 3C

CH3

CH3 N CH3

Et N Et

H 3C

Et

CH3 N

Et N NH O

Br

H 2N

7

NH O

3g

74

NH O

3h

59

3i

83

3j

81

3k

88

3l

90

3m

90

3n

94

3o

80

Br

H 2N

8

H 2N

9

H3CO

NH O

OCH3

H 2N

10

H 3C

NH O

CH3

11

NH O

H 2N O2N

H3CO

OCH3

H 2N

12

NH O

O2N EtO

O

13

H O2N

14

NH O

OEt

H 2N

O2N

CH3 N CH3

H 2N

H 3C

CH3 N NH O

O2N Cl

15

H 2N

NH O

Cl O2N

H3CO

H 2N

16

OCH3

OCH3 NH O

H3CO

3p

85

O2N aReaction

conditions: aldehyde (1 mmol), acetoophenone (1 mmol), anilines (1.1 mmol), GO (80 mg), TBAB (30 mol%), under solvent-free condition at 100 °C. bIsolated yield.

It is worth mentioning that the presence of electron-withdrawing groups on aldehydes and electron-donating groups on anilines resulted in better yields. Anilines with electron-donating alkoxy and alkyl groups reacted well under these conditions to give the desired products 3b-d in high yields. N,N-Dialkylbenzene-1,4-diamines (entries 5 and 6) also underwent sequential aldol coupling/aza-Michael addition with benzaldehyde 1a and acetophenone 2a to give the corresponding products 3e and 3f in 90 and 87% yields, respectively. As evident from the results, the position of the substituents, had a significant role in the reactivity of the aniline. For instance, when 2-bromoaniline was used to react with chalcone intermediate, only 74% of the desired β-amino ketones was observed owing to their steric hindrance. The use of higher steric hindrance aniline such as 2-isopropylaniline also led to low yield of the corresponding β-amino ketone 3h (entry 8, 59%) Anilines bearing electron-rich substituents (-OMe, -Me) on their meta-positions also gave the desired products 3i-j in high yields. It is worth mentioning that in the first step, replacement of benzaldehyde with 4-nitrobenzaldehyde led to the incremental improvements of the yield of chalcone formation. As expected, this improvement in chalcone formation, positively affected the final production of β-amino ketones (Table 2, entries 11-16). To study the role of the carboxylic acid groups of the GO catalyst, GO was treated with aqueous 0.1 N sodium hydroxide under stirring for 12 h at room temperature. Fourier transform infrared (FTIR) absorption spectroscopy was performed to analyze the functional groups in base-treated GO (Figure 1). The FTIR spectrum of b-GO showed that the intensity of carboxyl band at 1720 cm-1 decreased, while the new peak originates from the carboxylate group increased in intensity.39, 40 This spectral information confirmed the presence of carboxylate groups after the base treatment. When the model reaction was carried out using b-GO as a catalyst, it was found that the presence of carboxylate groups substantially suppressed the catalytic activity of b-GO. Finally, a control experiment was conducted to support the involvement of COOH groups of GO in the catalytic reaction. For this purpose, 1-pyrene-carboxylic acid was used as a model catalyst to mimic the graphene-based material. Gratifyingly, 1-pyrenecarboxylic acid resulted in

high yield of the catalytic model reaction while pyrene itself had no activity in the sequential aldol coupling/aza-Michael addition of amines to chalcones. This finding proved the crucial role of the π−π* backbone and acidic groups of GO in the catalytic action.40, 41

Figure 1. Normalized transmission infrared absorbance spectra of GO and b-GO

Furthermore, to determine whether metal impurities in GO were involved in this sequential reaction, the as-prepared GO was analyzed by inductively coupled plasma atomic emission spectroscopy (ICP-AES). The Mn content (used in the preparation of GO) was measured to be less than 40 ppb via ICP-AES which is nearly equivalent to other trace metal contaminants found in the material.22 The obtained results indicated that the metal impurities have no effect on the catalytic activity of GO. The recyclability of GO was tested for sequential aldol coupling/azaMichael addition of benzaldehyde 1a, acetophenone 2a and aniline under optimized reaction condition. The catalytic deactivation was observed after 6th cycle (Table 3).

Table 3: Reusability studya Run Yield of

3ab

1

2

3

4

5

6

84

84

83

82

82

80

aReaction

conditions: benzaldehyde (1 mmol), acetoophenone (1 mmol), aniline (1.1 mmol), GO (80 mg), TBAB (30 mol%), under solvent-free condition at 100 °C. bIsolated yield.

It should be noted that during the recycling experiments, the GO catalyst was recovered from the reaction mixture by simple filtration after previous runs, washed with warm ethanol several

times and dried in a vacuum before starting the next test. In order to evaluate the structure of the GO after 6 runs, Raman spectroscopy was taken for spent catalyst (Figure 2). The obtained Raman spectra of GO and recovered GO indicated the partial reduction of recovered GO after the last run. The G band red-shifted from 1593 cm-1 in the GO spectrum to 1581 cm-1 in the spectra for recovered GO while the ID/IG ratio increased from 0.97 for GO to 1.24 for recovered GO. Both the red-shift of the G band and the increase in the intensity ratio (ID/IG) can be attributed to the recovery of sp2 domains in the graphitic structure and is consistent with most chemical reduction reports.42,

43

The spent GO was also characterized by X-ray diffraction

method. As can be seen from Figure 2, the peak intensity at 11.53° decreased and a new broad peak with the maximum at 2θ = 26.46° appeared. The observation of characteristic d002 reflection of graphite at 26.46 indicated that the GO catalyst underwent partial reduction after 6th run.

Figure 2. Raman (left) and XRD (right) spectra of GO and recovered GO after 6th run Moreover, the as-prepared GO was measured to have a specific surface area of 23.3 m2g-1 using the BET method. The BET surface area of the recovered catalyst did not show obvious differences compared with the starting material. The plausible mechanism of this sequential aldol coupling/aza-Michael addition reaction is illustrated in Fig. 3. GO as a Brönsted acid catalyst facilitates in situ chalcone formation from the aldol product in an enol mechanism. Then chalcone I (which is activated via H-bond interaction between the protons in acidic heterogeneous catalyst (GO) and the carbonyl group) reacts with aniline to furnish intermediate II. Finally, a rapid tautomerization occurs to generate the azaMichael adduct III.

H

O GO Ar

CH3

GO O O

Ar

H

GO Ar' 1

CH2

Ar

H 2O

2a

GO

H2NAr''

O

Ar'

O

NH2Ar"

O

NHAr"

tautomerization Ar

Ar'

Ar

Ar'

GO

I

II

III

Figure 3. A plausible mechanism In summary, we demonstrated that GO in conjunction with tetra n-butyl ammonium bromide (TBAB) was able to catalyze one-pot sequential aldol coupling/aza-Michael addition of aromatic amines to chalcones in a single reaction vessel. The unique reactivity of GO facilitated access to β-amino ketones from a wide range of commercially available starting materials, and in the absence of metal catalysts. The obtained results showed that π−π* backbone and acidic groups in the GO are responsible for its high catalytic efficiency. The catalyst had good recyclability under solvent-free conditions without the formation of side products.

Acknowledgment The authors are grateful to the Shiraz University for their financial support. Conflict of interest The authors declare no conflict of interest.

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Graphical abstract

O Ar

H

O GO, TBAB, solvent-free, 100 °C

+

Ar

Ar Ar

Coupling reaction

aza-Michael addition

O H 3C

Ar

ArNH2

Advantages:  Metal- and solvent-free pathway  Heterogeneous catalyst  High yield of products  Rapid recycling protocol  Using a single reaction vessel

Ar

NH

O Ar

Highlights 

GO catalyzed sequential aldol coupling/aza-Michael addition of aromatic amines to chalcones



In situ generation of chalcones under solvent and metal-free conditions



Using of aromatic amines as weak nucleophiles in aza-Michael addition



Having easy and rapid recycling protocol for catalyst by filtration



Synthesis of β-amino ketones in high yields