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DOI: 10.1055/a-2564-4720
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Emerging Trends in Organic Chemistry: A Focus on India

Trimethylsilyl Triflate as an Efficient Catalyst for Intramolecular and Intermolecular Carbonyl–Alkyne Metathesis Reactions

Rohit Kumar Maurya
,
Ashutosh Dey
,
Vikash Kumar
,
Mahender Khatravath  ∗

The authors thank the DST-SERB India (CRG/2022/002217 and EEQ/2022/000198) for the financial support of this work.
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Abstract

Trimethylsilyl triflate has emerged as a powerful and versatile Lewis acid catalyst in organic synthesis, offering high efficiency under mild reaction conditions. It is known for its strong electrophilic activation and is widely used for C–C bond formation, heterocyclic synthesis, and protecting-group transformations. Herein, a straightforward synthesis of various biologically and synthetically important compounds, including 2H-chromenes, coumarins, furans, pyrans, and chalcones, has been achieved through carbonyl–alkyne metathesis reactions with trimethylsilyl triflate as a Lewis acid catalyst.


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Key words

carbonyl–alkyne metathesis - chromenes - coumarins - chalcones - trimethylsilyl triflate - organocatalysis

Carbonyl–alkyne metathesis (CAM) is one of the most efficient and sustainable methods for the formation of new C–C and C–O bonds.[1] The reaction involves the exchange of substituents between a carbonyl group and an alkyne, leading to the formation of a new complex molecular architecture.[2] This exclusive reactivity design has made CAM a highly relevant strategy across various industries, including petroleum, materials science, dyes, and pharmaceuticals, particularly in synthesizing heterocyclic frameworks and functionalized molecules.[3] The profound utility of CAM lies in its versatility, with reactions typically proceeding through a [2+2] cycloaddition of a carbonyl group with an alkyne, followed by a [2+2] cycloreversion through an oxetane intermediate. This reaction pathway permits the efficient and stereoselective construction of α,β-unsaturated carbonyl compounds through intermolecular CAM, providing valuable building blocks for organic synthesis.[4] Notably, the intramolecular CAM reaction is important as it provides access to a wide range of complex carbocyclic and heterocyclic scaffolds.[2] The ability to design substrates for these reactions allows chemists to explore new synthetic routes to create highly functionalized and biologically relevant molecules, pushing the boundaries of modern synthetic chemistry. As a result, the continued development of CAM reactions offers exciting prospects for creating novel compounds with potential therapeutic applications, further highlighting the significance of these reactions in pursuing more-efficient and more-sustainable chemical transformations.

Over the past few decades, advances in the field have established that the CAM reaction can be effectively promoted through two distinct pathways: activation of the carbonyl moiety through oxophilic Lewis or Brønsted acid catalysis or activation of the alkyne moiety by using a π-electrophilic Lewis acid catalyst.[5] An essential feature of CAM is its ability to form functionalized furans, indanones, quinolones, naphthothiophenes, carbazoles, indolizidines, pyrrolizidines, 2H-chromenes, and other oxygen- and nitrogen-based heterocycles with remarkable regio- and stereoselectivity.[6]

Typical oxophilic Lewis acids that have been used to activate the carbonyl group include FeCl3, GaCl3, SbF5, or a triflate salt of a metal such as Zn, Yb, In, or Sc (Scheme [1]; top).[5] [6] [7] Alternatively, Brønsted acids such as pTSA, TfOH, TFA, and HBF4 have also proven effective in activating carbonyl groups. The alkyne moiety can be activated by various π-electrophilic Lewis acids, including AgSbF6 and various Pd complexes.[6] Despite these developments, many CAM reactions still require harsh reaction conditions or high loadings of transition-metal catalysts. Moreover, several catalytic systems are limited to either intermolecular or intramolecular CAM reactions, with some leading to undesirable mixtures of stereoisomeric products.[2] , [4] [5] [6] Consequently, there is a growing need for the development of new catalytic systems that are not only selective and efficient but also environmentally friendly and versatile for both types of CAM reactions. Recent advances in CAM reactions include organocatalytic approaches using tropylium and iodine catalysts, offering enhanced efficiencies with lower catalyst loadings and improved reaction conditions (Scheme [1]; bottom).[6o] [r]

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Scheme 1 Previous approaches for carbonyl–alkyne metathesis

Trimethylsilyl triflate (TMSOTf) has emerged as a powerful and versatile Lewis acid catalyst in organic synthesis, offering high efficiency under mild reaction conditions. It is known for its strong electrophilic activation and it is widely used for carbon–carbon bond formation, heterocyclic synthesis, and protecting-group transformations. TMSOTf is particularly useful in catalyzing such reactions as aldol condensations, Diels–Alder cyclizations, and cascade annulations, which are essential for constructing complex molecular structures, especially those containing nitrogen or oxygen heterocycles.[7] Its high reactivity, easy availability, low catalyst loading, and compatibility with various substrates make TMSOTf a valuable tool in sustainable synthetic methods. This approach has proven highly effective in promoting both intramolecular and intermolecular CAM reactions.

Herein, we discuss the synthesis of various biologically and synthetically important compounds, including 2H-chromenes, coumarins, furans, pyrans, and chalcones from various substrates by using TMSOTf as a Lewis acid catalyst (Scheme [2]). This strategy ensures high efficiency and delivers remarkable yields and selectivities, making it a versatile and practical solution for constructing complex molecular frameworks. The adaptability of this catalyst to both types of CAM reactions marks a substantial improvement over previous methodologies, addressing limitations in substrate scope and reaction conditions.

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Scheme 2 TMSOTf-catalyzed carbonyl alkyne metathesis (CAM) reaction

To evaluate the feasibility of the designed strategy, a series of (propargyloxy)aryl aldehyde precursors were efficiently synthesized by the standard Sonogashira cross-coupling reaction of O-propargylated 2-hydroxy aldehydes with aryl iodides, following our previously reported protocol for the synthesis of chromenoisoxazoles.[8] Our initial examinations started with TMSOTf as a catalyst for the intramolecular CAM reaction of 2-[(3-phenylprop-2-yn-1-yl)oxy]benzaldehyde (1a) as the model substrate with various catalyst loadings, temperatures, and reaction times (Table [1]). In our initial investigation, 1a was reacted in the presence of 15 mol % TMSOTf in MeCN at room temperature for 12 hours. We were delighted to find that the desired product 2a was obtained, albeit in only 52% yield (Table [1], entry 1). To improve the yield of 2a, we conducted the reaction at 80 °C with TMSOTf catalyst loadings of 15 and 20 mol %. Fortunately, the yield of product 2a increased from 52 to 75% with the 20% loading (entries 2 and 3). Furthermore, solvents such as dichloromethane (DCM), CHCl3, THF, and DMF gave poor yields of the products (entries 4–7). Only traces of the product were obtained in methanol or toluene (entries 8 and 9). However, when the reaction was conducted in the presence of 15 mol% TMSOTf in DCE as the solvent at room temperature for 12 hours, the desired product 2a was obtained in a reasonable 63% yield (entry 10). This positive result prompted us to evaluate the effect of the temperature and the catalyst loading. When the same reaction was conducted at 80 °C for six hours, a drastic improvement in the product yield from 63 to 84% was observed (entry 11). Furthermore, when the catalyst loading was increased from 15 mol % to 20 mol % and the reaction was conducted at 80 °C for four hours, the product was obtained in an excellent 94% yield (entry 12). Reducing the catalyst loading to 10 mol % decreased the product yield (entry 13), whereas increasing it 25 mol % failed to improve the yield (entry 14). A control experiment without TMSOTf confirmed the need for the catalyst, as no product was observed after 18 hours in DCE at 80 °C (entry 15).

Table 1 Optimization of an Intramolecular CAM Reactiona

Entry

Solvent

TMSOTf (mol%)

Temp (°C)

Time (h)

Yieldb (%)

 1

MeCN

15

 Rt

12

52

 2

MeCN

15

 80

12

68

 3

MeCN

20

 80

12

75

 4

DCM

15

 Rt

15

20

 5

CHCl3

15

 Rt

15

18

 6

THF

15

 65

12

25

 7

DMF

15

100

15

18

 8

MeOH

15

 80

15

trace

 9

PhMe

15

110

15

trace

10

DCE

15

 Rt

12

63

11

DCE

15

 80

 6

84

12

DCE

20

 80

 4

94

13

DCE

10

 80

10

75

14

DCE

25

 80

 6

94

15

DCE

-

 80

18

–

a The reaction was performed on a 0.5 mmol scale of the limiting reactants in 10 mL of solution.

b Determined by column chromatography.

The optimized conditions (Table [1], entry 12) were successfully applied to a gram-scale synthesis of 2a with comparable efficiency to the smaller-scale reaction (Scheme [3a]). We then examined the scope of the protocol to produce a variety of 2H-chromene derivatives under the optimized conditions (Scheme [3a]). Initially, we investigated the impact of substituents on the aryl ring adjacent to the carbonyl group in 2-(propargyloxy)benzaldehydes. Pleasingly, substrates bearing an electron-donating 3-methyl group or an electron-withdrawing 3-bromo group reacted smoothly to afford the 2H-chromene products 2d and 2e, respectively, in good yields. Moreover, the protocol exhibited excellent compatibility with ortho-naphthyl functionalized substrates, delivering high yields of the tetracyclic products 2g–i. The influence of substituents attached to the alkyne moiety was also explored under the optimized reaction conditions. Arylalkynes bearing an electron-donating ortho-benzyloxy or para-methoxy group delivered the products 2c and 2f, respectively, in excellent yields. However, the introduction of electron-withdrawing CO2Me and NO₂ groups at the ortho- and para-positions, respectively, led to a reduction in yields of the corresponding products 2e and 2b. The substrate with an electron-withdrawing NO2 group in the meta-position gave a good yield of product 2d. Additionally, substrates with heterocyclic 2-thienyl, 3-pyridyl, or 9-phenylcarbazol-2-yl groups on the ortho-naphthyl functionalized substrate also reacted efficiently under the optimized conditions, forming the desired products 2g–i in good yields.

Zoom Image
Scheme 3 Scope of the intramolecular CAM

To check the reactivity of the ketones, the aldehyde was replaced with a ketone functionality. A ketone with an electron-withdrawing methoxycarbonyl group on the phenyl ring attached to the alkyne reacted to give product 2j, albeit in a reduced yield, whereas the corresponding substrate with an unsubstituted phenyl ring failed to react under the optimized reaction conditions.[9] These results highlight the significant impact of steric and electronic factors on the reaction efficiency.

2-(Propargyloxy)benzaldehyde without a substituent at the alkyne terminal failed to react, probably due to the formation of less-stable carbocation intermediates (see Scheme [5] and mechanistic discussion below). Indeed, we were able to use this reaction to transfer the 2-formylphenyl propiolate moiety to produce previously reported pharmacologically and photophysically active coumarin derivatives (Scheme [3b]).[10] This transformation highlights the versatility of our methodology in generating coumarins 4a and 4b, underlining its potential to advance research within these domains.

The applicability of the TMSOTf-catalyzed CAM protocol was further extended to the synthesis of 2,5-dihydrofurans and 5,6-dihydro-2H-pyrans under the optimized reaction conditions (Scheme [3c]). First, the effect of substituents on the aryl ring attached to the alkyne moiety of the (propargyloxy)acetaldehydes 6 was investigated for the formation of 2,5-dihydrofurans. Substrates bearing electron-donating OMe or Me groups in the ortho- and para-positions reacted efficiently, delivering products 7b–d in good yields. Interestingly, when the length of the carbon chain adjacent to the carbonyl group in the (propargyloxy)acetaldehyde was increased by one carbon atom, the reaction gave 5,6-dihydro-2H-pyrans as products. Moreover, (het)arylalkynes with an electron-withdrawing ethoxycarbonyl substituent in the para-position or containing a heterocyclic 2-thienyl group were also compatible, producing the desired products 7e and 7f, respectively, in moderate yields. However, the 4-(propargyloxy)but-2-enal 6g consistently failed to undergo the desired transformation under the optimized reaction conditions. This lack of reactivity could be attributed to the increased electronic effects introduced by the conjugated double bond in the but-2-enal structure. The conjugation probably destabilizes the reactive intermediate necessary for the cyclization process, thereby inhibiting the formation of the desired products. Additionally, the electron-density distribution in the substrate might not favor the activation by TMSOTf, further contributing to the failure of the reaction.

Zoom Image
Scheme 4 Scope of the intermolecular CAM

We then explored the application of TMSOTf as a catalyst in intermolecular CAM reactions, which are valuable synthetic tools for producing highly desirable α,β-unsaturated enones (chalcones). Following extensive optimization (for details, see the Supporting Information, p. 15), we identified the optimal condition as follows: reaction of the appropriate benzaldehyde or acetophenone with ethynylbenzene in a 1:2 ratio, with a catalytic load of 35 mol % TMSOTf in MeCN at 80 °C for 12 hours. We were pleased to find that, under these optimized conditions, TMSOTf effectively catalyzed intermolecular CAM reactions of aralkynes with carbonyl compounds with moderate efficiency (Scheme [4]). The level of efficiency aligns with that of known catalytic systems for intermolecular CAM reactions, which typically encounter challenges due to entropy loss.[2] [4] Notably, the reaction proceeded smoothly irrespective of the electronic properties of substituents on the aromatic ring of the carbonyl compounds (10a–e). Furthermore, the protocol was successfully extended to acetophenone as a substrate instead of benzaldehydes, permitting the synthesis of a biologically significant coumarin–chalcone derivative[10c] 10f; such compounds are challenging for other established CAM catalytic systems. To check the reactivity of substrates having basic groups, such as a hydroxy group, we have performed the intermolecular CAM reaction of salicylaldehyde with ethynylbenzene. However, under the optimized reaction conditions, the substrate remained unreactive. We believe that this lack of reactivity might be due to the quenching effect of the basic –OH group on TMSOTf, which could interfere with the reaction mechanism.[6r] This methodology offers an appealing alternative to conventional synthetic approaches, facilitating the preparation of chalcones from benzaldehydes or acetophenone and an aromatic alkyne.

Based on the observed results and the established chemistry of the CAM reaction, we propose the plausible mechanism shown in Scheme [5]. The process begins with the activation of the carbonyl group by the oxophilic Lewis acid TMSOTf, rendering it liable to nucleophilic attack by the alkyne. This interaction generates a vinylic carbocation intermediate B, a crucial step supported by the experimental observation that terminal alkynes fail to produce the desired product. In contrast, aryl-substituted alkynes, which stabilize the vinylic cation better than their alkyl-substituted counterparts, exhibit greater efficiency in this transformation. The vinylic cation undergoes intramolecular ring closure to form an oxetene intermediate C, which subsequently undergoes an electrocyclic ring-opening step to yield the final CAM product. This mechanism underscores the importance of electronic factors in determining the outcome of the reaction.

Zoom Image
Scheme 5 Proposed mechanism for the TMSOTf-mediated CAM reaction

In conclusion, we have demonstrated that TMSOTf is an efficient organic Lewis acid promoter for intramolecular and intermolecular CAM reactions.[11] This versatile catalytic activity, rarely exhibited by other established CAM approaches, was successfully applied to a broad range of substrates, permitting the synthesis of a diverse family of valuable organic structures. Key advantages of this protocol include mild reaction conditions, high atom economy, the use of inexpensive starting materials, and an environmentally friendly catalyst. This method not only demonstrates excellent substrate tolerance but also provides a streamlined approach to the synthesis of complex heterocyclic scaffolds with high efficiency. Additionally, this method enables the incorporation of carbonyl functionality into chromene frameworks. As a result, this approach affords a versatile and efficient route to functionalized 2H-chromenes, coumarins, 2,5-dihydrofurans, 5,6-dihydro-2H-pyrans, and chalcones, making it a powerful tool for the synthesis of biologically and photochemically active molecules.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgements

R.K.M., A.D., and V.K. are grateful to the Central University of South Bihar (CUSB) for their Ph.D. admissions. M.K. thanks DST-SERB India for supporting this work and CUSB-Gaya for providing the infrastructure.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2564-4720.
  • Supporting Information

Corresponding Author

Mahender Khatravath
Department of Chemistry, Central University of South Bihar
SH-7, Gaya Panchanpur Road, Karhara, Gaya-824236, Bihar
India   

Publication History

Received: 29 January 2025

Accepted after revision: 21 March 2025

Accepted Manuscript online:
21 March 2025

Article published online:
01 July 2025

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Zoom Image
Scheme 1 Previous approaches for carbonyl–alkyne metathesis
Zoom Image
Scheme 2 TMSOTf-catalyzed carbonyl alkyne metathesis (CAM) reaction
Zoom Image
Scheme 3 Scope of the intramolecular CAM
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Scheme 4 Scope of the intermolecular CAM
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Scheme 5 Proposed mechanism for the TMSOTf-mediated CAM reaction