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Synlett 2017; 28(10): 1227-1231
DOI: 10.1055/s-0036-1588152
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© Georg Thieme Verlag Stuttgart · New York

Potassium Hydroxide Catalysed Intermolecular Aza-Michael Addition of 3-Cyanoindole to Aromatic Enones

Jingya Yang*
a   College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, P. R. of China   Email: yangjy@nwnu.edu.cn
,
Tianyuan Li
a   College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, P. R. of China   Email: yangjy@nwnu.edu.cn
,
Hongyan Zhou
b   College of Science, Gansu Agricultural University, Lanzhou 730070, P. R. of China
,
Nana Li
a   College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, P. R. of China   Email: yangjy@nwnu.edu.cn
,
Dongtai Xie
a   College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, P. R. of China   Email: yangjy@nwnu.edu.cn
,
Zheng Li
a   College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, P. R. of China   Email: yangjy@nwnu.edu.cn
› Author Affiliations
Further Information

Publication History

Received: 04 January 2017

Accepted after revision: 12 February 2017

Publication Date:
28 February 2017 (online)

 
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Abstract

Indole is one of the utmost important heterocycles as it is an essential nucleus of many pharmaceutical compounds. Its aza-Michael reaction, however, is underdeveloped because of the moiety’s inherent characteristics. Here, a potassium hydroxide catalysed intermolecular aza-Michael reaction of 3-cyanoindole with aromatic enones is described. A variety of chalcone derivatives are well tolerated and afford the corresponding N-adducts in moderate to high yields. The use of a cheap catalyst, low catalyst loading, mild reaction temperature, and good substrate tolerance make this procedure a direct and facile method for the preparation of N1-functionalized indoles.


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Key words

Michael addition - enones - 3-cyanoindole - nitrogen heterocycles - regioselectivity

Indole and its derivatives have significant biological activities, and the indole moiety as a privileged structure is ubiquitous in natural products and pharmaceutical compounds.[1] There are two main strategies for the synthesis of indoles: construction of indole ring by de novo cyclization reactions[2] and modification of the indole framework itself.[2b] [3] Therein, functionalization of the indole nucleus is mainly taken place at the C3-, C2-, and N1-positions.[3] Among these, N1-position modification of indoles has mainly been achieved by transition-metal-catalysed N-arylation[3e] and N-alkylation.[3f] [4]

Aza-Michael reaction,[5] as an atom-economical reaction for construction of C–N bond, is undoubtedly a potential, ideal protocol to achieve N1-functionalization of indole. But, in sharp contrast to the progress in Michael addition of indoles at the C3-position, the aza-Michael addition of indole has been underdeveloped, probably because of the inherent nucleophilic characteristics of indole compounds.[3b] [d]

In this context, a few intramolecular aza-Michael reactions of indoles have been successfully established.[6] Still, intermolecular aza-Michael reactions of unsubstituted indoles are mainly focused on highly active Michael acceptors such as acrylonitrile,[7] acrylates,[7] [8] and acrylamide.[7] Recently, copper-catalysed aza-Michael addition of indole to phenyl vinyl sulfones has also been documented.[9] However, the reaction of indole with relatively inert α,β-unsaturated ketones, especially aromatic enones, are rarely reported. To the best our knowledge, up to now, only one example of direct aza-Michael reaction of indole with chalcone is reported by Deka et al. using In(OTf)3 as catalyst under microwave irradiation.[10] The indirect strategies are conjugate addition–oxidation of indoline[11] or reaction of indole with α,β-unsaturated alkynol.[12] But, an equivalent amount of Cs2CO3 or DBU was needed, and sometimes, mixtures of C3- and N1-adducts were obtained inevitably.[12] Therefore, it would be extremely desirable to develop effective protocols to access aza-Michael reaction of indoles with aromatic enones.

Recently, we have successfully developed the aza-­Michael reactions of pyrazole[13] and indazole[14], bearing less acidic N–H bond (pyrazole: pK a = 14.21, indazole: pK a = 13.86),[15] with α,β-unsaturated ketones under mild conditions. However, when indole was used as nucleophile to react with chalcone under these conditions, no reaction occurred at all. This probably due to the very weak N–H acidity of indole (pK a = 16.97).[15] Literature reports indicate that the pK a value of the NH proton can be reduced by introducing an electron-withdrawing substituent.[3b] [d] [16] Inspired by this, we proposed introducing an electron-withdrawing group to indole at C3-position to improve its N1-nucleophilicity, thereby assisting realizing its aza-Michael reaction with α,β-unsaturated ketones.

Based on the above consideration, 3-cyanoindole became our first choice. First, 3-cyanoindole itself and its N1-derivates have important biological activities such as inosine monophosphate dehydrogenase (IMPDH) inhibitory activity.[17] Next, 3-cyanoindole can be transferred into a broad range of functional compounds, such as aldehydes,[18] carboxylic acids,[19] amides,[20] ketones,[21] and heterocycles.[22] More important, 3-cyanoindole is a key intermediate to synthesize natural products (topsentin A and nortopsentins B and D)[23] and diverse pharmaceutical compounds such as sphingosine kinase inhibitor,[24] anticancer agents,[25] glycogen synthase kinase 3β inhibitors,[26] and 5-HT3 antagonists.[27] In addition, 3-cyanoindole can be prepared conveniently.[28]

Though transition-metal-catalysed N-arylation,[29] N-allylation,[30] and N-alkenylation[31] of 3-cyanoindole have been achieved successfully, aza-Michael reaction of 3-cyanoindole is found in only one example with methyl propiolate.[32] Here, we have developed a KOH-catalysed intermolecular aza-Michael addition of 3-cyanoindole with aromatic enones under mild conditions.

Initially, the reaction of 3-cyanoindole with chalcone 1a was chosen as a model reaction to optimize the reaction conditions (Table [1]). Not surprisingly, none of the desired product 2a was obtained in the absence of catalyst (Table [1], entry 1). When several commercially organic bases were screened, only DBU showed some activity and gave the desired product 2a in 10% yield after nine hours (Table [1], entries 2–4). Then, a series of inorganic bases were investigated (Table [1], entries 5–11). While most of them did not show effective catalytic activity (Table [1], entries 5–9), KOH and KOt-Bu promoted the reaction efficiently to furnish the desired product 2a with acceptable yield (Table [1], entries 10, 11). Therein, the best result was obtained when KOH was used, which gave 2a in 68% yield (Table [1], entry 10). Next, the effect of solvent on the reaction was evaluated (Table [1], entries 12–20). Unfortunately, no reaction occurred at all in THF, DMF, DMSO, and EtOH. The other tested solvents afforded the product 2a in less-than-desirable yields. Further investigation showed either increasing or decreasing of the reaction temperature resulted in an inferior result (Table [1], entries 21, 22). Unexpectedly, when the catalyst loading was increased, the product was achieved with unfavourable yield (Table [1], entries 23, 24). Thus, the best conditions for this reaction have been established as 5 mol% of KOH as catalyst in CH2Cl2 at 25 °C.

Table 1 Optimization of the Reaction Conditionsa

Entry

Catalyst

Solvent

Temp (°C)

Yield (%)b

 1

–

CH2Cl2

25

 0

 2

DBU

CH2Cl2

25

10

 3

DMAP

CH2Cl2

25

 0

 4

TMG

CH2Cl2

25

 3

 5

Na2CO3

CH2Cl2

25

trace

 6

K2CO3

CH2Cl2

25

 0

 7

Cs2CO3

CH2Cl2

25

trace

 8

LiOH

CH2Cl2

25

 0

 9

NaOH

CH2Cl2

25

 6

10

KOH

CH2Cl2

25

68

11

KOt-Bu

CH2Cl2

25

50

12

KOH

CHCl3

25

15

13

KOH

DCE

25

32

14

KOH

toluene

25

trace

15

KOH

1,4-dioxane

25

10

16

KOH

THF

25

 0

17

KOH

MeCN

25

30

18

KOH

DMF

25

 0

19

KOH

DMSO

25

 0

20

KOH

EtOH

25

 0

21

KOH

CH2Cl2

40

43

22

KOH

CH2Cl2

 0

 5

23c

KOH

CH2Cl2

25

51

24d

KOH

CH2Cl2

25

30

a Reaction conditions: 1a (0.30 mmol), 3-cyanoindole (0.36 mmol), catalyst (5 mol%), solvent (3 mL), 9 h.

b Isolated yield.

c KOH (10 mol%).

d KOH (1.0 equiv).

With the optimized reaction conditions in hand, the substrate scope of aromatic enones was examined (Table [2]).[33] A variety of readily available chalcone derivatives with different substituents were allowed to react with 3-cyanoindole. Except for 1i, they were well tolerated to the optimal reaction conditions, and afforded the corresponding products 2a–h and 2j–s in moderate to high yields (Table [2], entries 1−19). In detail, when R2 was phenyl and R1 was para-substituted phenyl, electron-withdrawing substituents gave the corresponding products in slightly higher yields than electron-donating substituent (Table [2], entries 2–5, 2b–e). When R1 was meta-substituted phenyl, the desired products 2f and 2g were afforded in high yields (Table [2], entries 6, 7). When R1 was ortho-substituted phenyl, 2-chlorochalcone 1h gave the target compound 2h in 58% yield (Table [2], entry 8), but 2-methoxychalcone 1i did not reacted at all (Table [2], entry, 9). This can probably be attributed to the steric hindrance. When R1 was para-substituted phenyl or phenyl and R2 was para- or meta-substituted phenyl, no obvious substituent effect was observed (Table [2], entries 10–19, 2j–s). Besides, heteroaryl enone 1t was viable under the optimal conditions, but the product 2t was obtained only with 26% yield (Table [2], entry 20).

Table 2 KOH-Catalysed Aza-Michael Reaction of 3-Cyanoindole with Aromatic Enonesa

Entry

R1

R2

Time (h)

Product

Yield (%)b

 1

Ph

Ph

 9

2a

68

 2

4-MeC6H4

Ph

 7

2b

48

 3

4-O2NC6H4

Ph

12

2c

57

 4

4-F3CC6H4

Ph

 7

2d

66

 5

4-ClC6H4

Ph

10

2e

57

 6

3-MeC6H4

Ph

 8

2f

70

 7

3-BrC6H4

Ph

 4

2g

75

 8

2-ClC6H4

Ph

10

2h

58

 9

2-MeOC6H4

Ph

10

2i

 0

10

4-MeC6H4

4-MeOC6H4

 9

2j

47

11

4-F3CC6H4

4-MeOC6H4

10

2k

60

12

4-FC6H4

4-MeOC6H4

10

2l

70

13

4-ClC6H4

4-MeC6H4

 6

2m

48

14

4-ClC6H4

4-MeOC6H4

 6

2n

58

15

4-F3CC6H4

4-ClC6H4

 6

2o

55

16

Ph

4-MeOC6H4

 6

2p

64

17

Ph

4-BrC6H4

 7

2q

53

18

Ph

4-ClC6H4

 7

2r

65

19

Ph

4-O2NC6H4

 6

2s

55

20

furan-2-yl

Ph

 8

2t

26

a Reaction conditions: enone 1 (0.30 mmol), 3-cyanoindole (0.36 mmol), KOH (5 mol%), CH2Cl2 (3 mL), 25 °C.

b Isolated yield.

The structure of product 2m was confirmed by X-ray crystallographic analysis (Figure [1]),[34] which further ascertained the N1-selectivity of this reaction. Moreover, we found that indole could not react with chalcone at standard conditions, which demonstrates the important role of cyano group.

To demonstrate the synthetic utility of the current protocol, the reaction between enone 1g and 3-cyanoindole was performed on a gram scale under the standard reaction conditions. As outlined in Scheme [1], following the general procedure, the reaction proceeded well to afford the corresponding adduct 2g in 69% isolated yield, which was similar to those observed in a previous investigation (Table [2], entry 7).

Zoom Image
Figure 1 X-ray crystal structure of 2m
Zoom Image
Scheme 1 Gram-scale experiment

In summary, we have developed a convenient method for the intermolecular aza-Michael reaction of 3-cyanoinole with aromatic enones using 5 mol% of KOH as catalyst. To overcome the site-selective problem of Michael addition of indole to aromatic enones, 3-cyanoinole was selected to achieve the N1-selectivity and satisfactory results were obtained. The approach shows good functional-group tolerance, in which a variety of chalcone derivatives are suitable substrates and give the desired N-adducts in moderate to high yield. Other merits of this strategy include use of a cheap and commercially available catalyst, low catalyst loading, and mild reaction temperature. The application of the current reaction to the synthesis of medicine containing heterocycles is now under investigation.


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No conflict of interest has been declared by the author(s).

Acknowledgment

The authors thank the National Nature Science Foundation of China (21362034 and 21462038), Research Fund for the Doctoral Program of Higher Education of China (20136203120005), and Key Laboratory of Eco-Environment-Related Polymer Materials for Ministry of Education for financial support.

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org.accesdistant.sorbonne-universite.fr/10.1055/s-0036-1588152.
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Zoom Image
Figure 1 X-ray crystal structure of 2m
Zoom Image
Scheme 1 Gram-scale experiment