Gold‐Catalyzed Highly Regioselective Coupling Reaction between

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group tolerance, the use of stoichiometric amounts of strong bases ... carbonyl coupling to form conjugated enones regioselective- ly. ... gold catalysed reaction of aldehydes and alkynes which is very ... Initially to test our curiosity, we checked the reaction of 4- .... catalyzed coupling reactions, Grignard reactions etc. Unfortu-.
DOI: 10.1002/slct.201800371 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57

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Gold-Catalyzed Highly Regioselective Coupling Reaction between Alkynes and Aldehydes for the Synthesis of Conjugated Enones Vanajakshi Gudla,*[a] Kolukuluri Chaguru Swamy,[a] and Venkateswara Rao Battula*[b] An efficient AuCl3/AgSbF6-catalysed enone synthesis from coupling of alkynes and aldehydes has been presented. The present reaction is very effective, simple and mild and has wide range of substrate scope. Both aryl (electron rich and electron deficient) and aliphatic aldehydes and terminal and internal

Introduction Enones especially a,b–unsaturated carbonyls are important structural frames-works seen in several bioactive natural products which are known to exhibit wide range of pharmaceutical and biological activities (see Figure 1 for some representative examples).[1] They are not only useful as scaffolds for the synthesis of biologically important molecules,[2] they are also one of the most useful building blocks in organic synthesis and even in functional organic materials.[3] Subsequently, significant efforts have been made over the decades to develop highly efficient synthetic strategies for the preparation of a,bunsaturated carbonyls. For carbonyl olefination, broadly utilised method is Wittig reaction. But this method faces problem due to the production of triphenylphosphine oxide in stoichiometric amount. Aldol reaction has also been used for the synthesis of enones which has its own disadvantage that it needs often an enolate precursor to achieve the desired regioselectivity.[4] Another important method for their synthesis is ClaisenSchmidt condensation reaction which needs strong base to promote the condensation reaction. All these methods in general require strong basic medium and therefore functional group tolerance and selectivity issues can be problematic. Likewise, most of the methods suffer from one or more limitations, such as poor substrate scope, limited functional group tolerance, the use of stoichiometric amounts of strong bases, production of byproducts or side products etc. Owing to their varied pharmacological activities and synthetic utility, the

[a] Dr. V. Gudla, Dr. K. C. Swamy Department of Organic Chemistry, Andhra University, Visakhapatnam 530003, India E-mail: [email protected] [email protected] [b] Prof. V. R. Battula Department of Engg. Chemistry, Andhra University, Visakhapatnam 530003, India E-mail: [email protected] Supporting information for this article is available on the WWW under https://doi.org/10.1002/slct.201800371

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arylalkynes participated smoothly in the reaction and provided exclusively trans product. This simple reaction can be coupled with other gold catalysed transformations which involve enones as substrates for further development.

development of efficient method for the synthesis of a,bunsaturated ketones is highly desirable. Metathesis reaction of carbonyls with alkynes by cleavage of the aldehyde C=O bond and formation of new C=C and C=O bonds to furnish enones[5] is known to overcome the most of the above said limitations, and it has also received attention because of the atomeconomical process alternative to the Wittig reaction and still the search for best catalyst is continued. Among the reported results, both oxophilic (activates aldehydes, for example SbF5, GaCl3, In(OTf)3, Yb(OTf)3, FeCl3, TMSOTf or SnCl2) and carbophilic Lewis (activates alkyne, for example Ag, Au etc.) acids are known to promote this transformation. Krische et al. reported the silver (AgSbF6) catalyzed intra- and intermolecular alkynecarbonyl coupling to form conjugated enones regioselectively.[5e] Although yields are good, reaction works under harsh conditions. Later, Yamamoto et al. reported the intramolecular heteroenyne metathesis of 1,3-enynyl carbonyls to give dieneones which further underwent Nazarov cyclization under gold catalysis.[6] But they did not study the intermolecular version of gold catalysed reaction of aldehydes and alkynes which is very useful transformation. The growing synthetic importance of chalcones demands alternative methods to access them under mild reaction conditions. Hence, we envisioned that cationic gold(III) could be used to activate alkynes and subsequently couple with aldehyde, similar to the silver catalyst described above in the coupling reaction between alkynes and aldehydes but under mild conditions with increasing yields. Gold catalysis has become one of the top most areas in organic synthesis and has occupied the position of Hot Topics in major journals and reviews due to variety of transformations and applications in total synthesis, green chemistry, electrochemistry etc.[7] While studying the catalytic properties of gold in organic syntheses to study and enhance the scope of gold catalysis, it was found that the reactions of arylacetaldehydes with arylalkynes under gold catalysis provided naphthalene derivatives.[8] Here, oxo and alkynophilicity of gold played crucial role in activating carbonyl and alkyne functions respectively. We were curious to check the reactivity of 4576

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Figure 1. Some representative examples of biologically important chalcones

aldehydes other than arylacetaldehydes i. e. substituted benzaldehydes and aliphatic aldehydes with arylalkynes under the same reaction conditions. It was found that, under gold catalyzed reaction conditions, aldehydes reacted with arylalkynes to furnish a,b–unsaturated ketones in an efficient manner (Scheme 1). We wished to make the intermolecular

Scheme 1. Gold-catalyzed coupling of aldehydes with arylalkynes to enones

reaction of aldehydes and arylalkynes facile in terms of yields and reaction conditions with cationic gold catalyst. Naphthalenes were obtained from arylacetaldehydes and arylalkynes in refluxing dichloromethane using combination of AuCl3 and AgSbF6[8] whereas the same catalytic system afforded enones from simple aldehydes and alkynes at RT itself. Here we report the details of gold catalyzed intermolecular enone synthesis from aldehydes and alkynes.

Results and Discussion Initially to test our curiosity, we checked the reaction of 4nitrobenzaldehyde (1 a, 1.0 equiv.) with 1-phenyl-1-propyne (2 a, 1.2 equiv.) in dry dichloromethane solvent under AuCl3/ 3AgSbF6 (2 mol %) catalysis at RT. Gratifyingly, reaction went smoothly and resulted in the formation of trans-enone 3 a in excellent yield (91%) at RT itself (Scheme 2). The same catalytic system (AuCl3/AgSbF6) for intramolecular version as reported by Yamamoto’s group[6] did the conversion at 100 8C in toluene solvent whereas surprisingly the present intermolecular version took place at RT itself in dichloromethane solvent. Next, we continued our checking under the similar conditions for generality and study of substrate scope. Aliphatic and aromatic aldehydes 1 were subjected to react with arylalkynes 2 under gold catalyzed reaction conditions. Both reacted well under the conditions to result in respective enones 3. Aliphatic and aromatic aldehydes resulted in comparable yields. Yields were excellent in most of the cases and transchalcone was the exclusive product (Table 1). Geometry of double bond was determined by comparison of NMR data of previous reports.[5e] Crude 1H NMR was taken to check the presence of any trace amount of cis-chalcone. To our delight, we could not trace any cis-isomer. Mono and disubstitutted arylaldehydes were participated in the reaction and aryl aldehydes having electron donating group (such as –OMe, alkyl) as well as electron withdrawing groups (Such as -NO2, -F, -Cl) did work well and yielded the corresponding enones. For

Scheme 2. Gold catalyzed reaction of 4-nitrobenzaldehydes with 1-phenyl-1-propyne.

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Table 1. Gold catalysed reactions of aldehydes with arylalkynes to give a, b-unsaturated ketonesa

Entry

Aldehyde (1)

Alkyne (2)

Enone (3)

Yield (%)b

1

91

2

93

3

89

4

86

5

92

6

87

7

89

8

93

9

89

10

88

11

91

12

NR



a

All reactions were carried out with 1 (1.0 equiv.), 2 (1.2 equiv.), AuCl3 (2 mol %) and AgSbF6 (6 mol %) in CH2Cl2 (3 mL/mmol of 1) at RT and reaction generally takes 3 h. bIsolated yield

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further extension, internal and terminal arylalkynes were employed to increase the scope of the reaction. Neither substituent position, nor electronic nature much influences the rate and yield of the reaction significantly. Reaction with AgSbF6[5e] needed heating conditions like 50–80 8C temperature, more amount of catalyst (10 mol %) and needed longer reaction time (generally 16 h) where as the present gold catalyst makes the reaction facile in terms of reaction conditions. Another note worthy point is that, in AgSbF6 catalysed intermolecular metathesis, 3.0 equiv. of aldehyde and 1.0 of alkyne were taken where as in the present gold catalysed reaction they are 1.0 equiv. and 1.2 equiv. respectively. In addition to this, silver catalyzed reaction of terminal alkynes such as phenylacetylene resulted in less yields[5e] while with gold catalyst reaction worked well with terminal alkynes also (entries 5–7) which reveals that AuCl3/3AgSbF6 catalytic system is more efficient and superior than AgSbF6 alone and other catalysts and makes the reaction facile. Reaction of aldehydes having halogen substitution (entries 4, 7, 8 and 11) especially bromo group (entry 11) are very attractive as the resulting products can be utilised for further transformation like metal catalyzed coupling reactions, Grignard reactions etc. Unfortunately, reaction of aliphatic alkyne trimethylsilyl acetylene failed to participate in this reaction (entry 12). Further, reaction was attempted with diphenylacetylene which is diaryl and internal alkyne, but it resulted in multiple products as found out from TLC observation. Study is under progress for the reactions between diaryl alkynes and aldehydes/ketones. The regioselectivity giving exclusively trans-product may be explained by the mechanism proposed by Krische et. al.,[5e] and Yamamoto et. al.[6] i. e. via [2 + 2] cycloaddition followed by cycloinversion. Cationic gold coordination to alkyne triple bond followed by carbonyl function of aldehyde leads to formation of oxetenium intermediate in which subsequent ring opening expels enone. Since gold catalyst can perform a variety of conversions in molecules having C C unsaturation, this present reaction can be coupled with such reactions to find more gold catalyzed tandem reactions for the formation of complex molecules. The method could be exploited for further synthetic manipulations also due to the presence of unsaturation, ketone functionalities in the product and presence of halogen group when halo aryl aldehyde is employed as reaction partner.

Conclusions AuCl3/3AgSbF6 system very effectively catalyses intermolecular reaction of aldehydes other than arylacetaldehydes with arylalkynes led to the formation of enones. This reaction has wide scope as both internal and terminal arylalkynes can be used and takes place at room temperature itself. The present conversion is atom-economic. It may find applications in organic synthesis involving chalcone or enone synthons. Since gold catalyst can perform a variety of conversions, this present reaction can be coupled with such reactions to find out more gold catalyzed tandem reactions. Studies in this direction are currently under process.

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Acknowledgements Vanajakshi G. thanks SERB, India for fellowship and research grants provided for work. Also, the authors thank Andhra University, Visakhapatnam, India for providing facilities to carry out research work.

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Submitted: February 8, 2018 Revised: April 6, 2018 Accepted: April 11, 2018

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