Tandem indium(III)-catalyzed cyclization and intermolecular hydrofunctionalization of 1,6-enynes

Abstract

A tandem indium(III)-catalyzed cyclization and intermolecular hydrofunctionalization of 1,6-enynes for the stereoselective synthesis of functionalized carbo- and heterocycles is reported. The synthetic transformation involves a regio- and stereoselective 5-exo-dig 1,6-enyne cyclization followed by intermolecular nucleophilic addition of alcohols (including water), carboxylic acids, arenes and trimethylsilyl azide. Remarkably, the reaction proceeds under mild reaction conditions with low catalyst loading using inexpensive commercial indium(III) halides, affording good yields with broad chemoselectivity and high regio- and stereoselectivity.

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Introduction

Metal-catalyzed 1,n-enyne cyclizations provide an efficient and atom-economical method for the synthesis of architecturally complex cyclic frameworks, with generally good levels of regio- and stereoselectivity and reasonable versatility.¹ In addition, tandem processes in which a nucleophilic addition occurs after the cyclization step provide direct access to more elaborate chemical structures in a single operation.² This chemical transformation starts with the electrophilic activation of the alkyne (π-acid catalysis), although the reaction mechanism varies depending on the metal catalyst.³ Usually, catalysis is associated with precious transition metals such as palladium, platinum, and gold due to their unique chemical properties.⁴ However, some main group elements, particularly post-transition metals such as indium, gallium and bismuth have been postulated as valuable and economical alternatives, although their reactivity and synthetic utility are still underexplored.⁵

Indium(III) is a low-cost Group 13 element with attractive chemical properties for catalysis.⁶ Its larger size compared to boron or aluminum renders it as a softer Lewis acid with oxophilic and carbophilic character, enabling dual catalytic activity. Over the years, indium(III) has proven to be an effective σ-Lewis acid in fundamental organic transformations such as Diels–Alder cycloadditions or carbonyl additions, and more recently as a π-acid in the electrophilic activation of C–C unsaturated bonds, mostly alkynes.⁷ Interestingly, the alkynophilicity can be tuned through ligand modification, although only a small number of synthetic examples have been developed to date.⁸ In this field of research, we have recently shown indium(III) iodide as a particularly efficient π-acid catalyst in intramolecular alkyne hydroarylation, hydroalkoxylation and hydroamination reactions.⁹ The cycloisomerization reaction of enynes under indium(III) catalysis was first studied by Chatani,¹⁰ showing that 1,6-enynes react with 5-exo-dig regioselectivity, affording a variable mixture of cyclopentene dienes through a metathesis skeletal rearrangement (Scheme 1a).¹¹ The power of indium(III) catalysis, particularly cationic indium(III) iodide, in enynic cyclizations was highlighted by Corey in the synthesis of polycyclic structures through cascade polyenyne cyclization reactions.¹² In addition, our group has also reported In(III)-catalyzed enyne cyclizations such as the regio-, stereoselective and stereospecific synthesis of tricyclic frameworks by tandem indium-catalyzed cyclization/hydroarylation of aryl 1,5-enynes and 1,6-enynes with excellent chemoselectivity (Scheme 1b).¹³ Herein, we disclose the first tandem 1,6-enyne cyclization and intermolecular nucleophilic addition under indium(III) catalysis. This approach demonstrates the feasibility of trapping the cycloisomerization intermediate with an external nucleophile under In(III) catalysis, broadening the synthetic utility of main group metals in the electrophilic activation of C–C unsaturated bonds under π-acid catalysis. Although these synthetic transformations have been reported under transition metal catalysis, this communication uncovers the first such examples using main group element catalysis.²

Scheme 1 Previous and current research on In(III)-catalyzed 1,6-enyne cycloisomerization reactions.

Results and discussion

According to our previous experience,^13b our research started by exploring the indium(III)-catalyzed 1,6-enyne cycloisomerization of 1 in the presence of methanol as an external nucleophile with the aim to trap the proposed zwitterionic cyclopropyl-like intermediate formed during the cycloisomerization (Scheme 2). Interestingly, the treatment of 1 with 5 mol% InI₃ in toluene (0.035 M) and MeOH (5 equiv.) at 80 °C afforded the methoxycyclization product 3a in 56% isolated yield in just 3 h along with cycloisomerization product 1a (entry 1, Table 1). The reaction also proceeded using CH₂Cl₂ as the solvent at 23 °C with the same chemical yield and short reaction time (entry 2). However, increasing the concentration (0.1 M in CH₂Cl₂) at 23 °C only produced a mixture of cycloisomerization products (1a and 1b) (entry 3). On the other hand, a larger excess of methanol inhibited the catalytic reaction at 23 °C even with 20 mol% InI₃ (entry 4), while 10 equiv. of MeOH and InI₃ in CH₂Cl₂ at 23 °C gave 3a in 72% yield (entry 5). Catalysis using the indium diiodonium cation (InI₂⁺) generated by treatment of InI₃ (5 mol%) with AgSbF₆ (5 mol%) provided 3a in a modest 32% yield (entry 6). On the other hand, In(OTf)₃ or In(NTf₂)₃ (5 mol%) produced a complex mixture of products (entries 7 and 8). Finally, we found that setting up the reaction at −20 °C and slowly warming up to 23 °C prevents the skeletal rearrangement, giving rise to the desired product 3a in 80% isolated yield in just 4 h (entry 10).

Scheme 2 Indium(III)-catalyzed cyclization/intermolecular hydrofunctionalization reactions of 1,6-enynes 1 and 2. ^aIsolated yields; ^b10 mol% catalyst employed.

Table 1 In(III)-catalyzed methoxycyclization of 1,6-enyne 1

Entry	InX3 ^a	T (°C)	Solvent	MeOH^b	t ^c (h)	Yield^d
a 5 mol% except entries 4 (20 mol%) and 5 (10 mol%).b Equivalent amount with respect to 1,6-enyne.c Monitored by TLC.d Isolated yield (%).e 0.1 M CH2Cl2.f Using AgSbF6 (5 mol%) as a cocatalyst.
1	InI3	80	Toluene	5	3	56
2	InI3	23	CH2Cl2	5	3	56
3	InI3	23	CH2Cl2 ^e	5	24	—
4	InI3	23	CH2Cl2	50	72	nr
5	InI3	23	CH2Cl2	10	24	72
6	InI3 ^f	23	CH2Cl2	5	4	32
7	In(OTf)3	23	CH2Cl2	5	24	—
8	In(NTf2)3	23	CH2Cl2	5	24	—
9	InI3	−20	CH2Cl2	5	24	nr
10	InI3	−20–23	CH2Cl2	5	4	80

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With the optimal reaction conditions in hand, we explored the versatility of the protocol by employing other organic nucleophiles and 1,6-enynes (Scheme 2). Starting from alcohols, we were delighted that the alkoxycyclization of 1 could be extended to the allylic alcohol 3-methyl-2-buten-1-ol, or phenol which were regioselectively incorporated with good yields (3b–d, 47–86%). In addition, the hydroxycyclization was successfully achieved using tap water as a nucleophile, giving rise to the corresponding alcohol 3e (86%). These results demonstrate the synthetic utility of indium(III) catalysis in hydroxy- and hydroalkoxylations of 1,6-enynes, providing novel examples uncovered under transition metal catalysis. Encouraged by these results, we tested carboxylic acids as nucleophiles for a selective hydroacyloxylation reaction which has been elusive using transition metal catalysis. Gratifyingly, following the previous experimental protocol developed, we found that indium(III) iodide catalyzed this tandem intermolecular transformation efficiently with a variety of novel aromatic and aliphatic carboxylic acids such as benzoic acid, cyclohexane carboxylic acid, 3,3-dimethylacrylic acid or pivalic acid, giving rise to a novel set of esters (3f–i) in moderate yields (45–53%). The compatibility of indium(III) catalysis with the carboxylic acid functional group is highly remarkable.

Next, we focused our attention on the tandem intermolecular addition using arenes as external nucleophiles. We were pleased to find that the tandem intermolecular cyclization/hydroarylation reaction using 1,3,5-trimethoxybenzene afforded 3j in 61% yield and the reaction with N-methylindole gave the corresponding product 3k in 92% yield. Our efforts to perform the hydroamination reaction using amines resulted in poor yields, but the versatile azide functional group was introduced using TMSN₃ and 10 mol% InI₃ (3l, 60%, Scheme 2).¹⁴ Overall, we demonstrate that the tandem indium(III)-catalyzed cyclization of 1,6-enynes and intermolecular nucleophilic addition can be performed with alcohols, carboxylic acids, arenes or the azide ion regioselectively (5-exo-dig) with good yields. As the next step, we planned to extend this methodology to other 1,6-enynes like 2 bearing an N-tosyl group as the 1,6-enyne bridge. As previously, the tandem reaction also took place efficiently with 5-exo-dig regioselectivity with a variety of oxygenated nucleophiles such as methanol or benzyl alcohol, carboxylic acids such as benzoic acid, or arenes such as 1,3,5-trimethoxybenzene or N-methylindole, affording the corresponding pyrrolidines 3m–q in 43–76% yields.

To explore the synthetic scope and stereoselectivity of this novel tandem indium(III)-catalyzed intermolecular nucleophilic addition to 1,6-enynes, we tested the styryl 1,6-enyne 4 presenting a 1,2-disubstituted alkene. Under the previously optimized reaction conditions, we found that the treatment of (E)-4 with InI₃ (5 mol%) and benzyl alcohol (5 equiv.) in CH₂Cl₂ at 23 °C gave the desired benzyloxycyclization product 5a in 75% isolated yield as a single diastereoisomer.¹⁵ Analogously, the reaction of benzoic acid also provided the diastereomerically pure benzoate 5b in 62% yield. In addition, the reaction using N-methylindole or 1,3,5-trimethoxybenzene as nucleophiles afforded the expected cyclopentenes 5c and 5d stereoselectively in 88 and 78% isolated yields with complete diastereoselectivity. Furthermore, the reaction using TMSN₃ also gave the azide 5e derivative in 80% yield.

Furthermore, the stereochemical outcome of this diastereoselective 1,6-enyne cyclization was explored using (Z)-1,6-enyne 4. Under the same experimental conditions, (Z)-4 showed lower reactivity than (E)-4, and an increase in the temperature up to 60 °C and extension of the reaction time (24 h) were necessary for a complete conversion. Interestingly, the tandem reaction using different organic nucleophiles such as benzyl alcohol, benzoic acid, 1,3,5-trimethoxybenzene or trimethylsilyl azide also gave the expected reaction products 5a–e as single diastereoisomers in 25–75% yields (Scheme 3). Distinct from the indium-catalyzed intramolecular sequence (Scheme 1b),^13b this transformation was stereoconvergent, probably due to the thermal isomerization of the chiral intermediate during the 1,6-enyne cyclization through an open carbocation structure, as deduced by monitoring the reaction of (Z)-4 with 1,3,5-trimethoxybenzene at different temperatures using ¹H NMR (see the SI). This behaviour contrasts with the stereospecific outcome observed under platinum(II) or gold(I) catalysis.^2a,j

Scheme 3 Diastereoselective In(III)-catalyzed cyclization/intermolecular hydrofunctionalization reactions using 1,6-enynes (E)-4 and (Z)-4. ^aReactions set up at −20 °C and heated to 60 °C in DCE.

To shed light on the mechanism of this tandem process, some experiments with deuterated 1,6-enyne 1 and nucleophiles were performed. Under the previously developed reaction conditions, the reaction of 1 with deuterated methanol gave (E)-3a-d₄ as a single stereoisomer in 74% yield (Scheme 4a).¹⁶ In addition, the reaction of 1,6-enyne deuterated at the terminal alkyne 1-d₁ (91% D) with non-deuterated methanol, under the same reaction conditions, gave (Z)-3a-d₁ in 65% yield and identical deuterium percentage (91% D, Scheme 4b). These overall results are in accordance with a trans-attack of the alkene on the (η²-alkyne)-indium complex and demonstrate that the carbon–deuterium bond is not broken throughout the cyclization process.

Scheme 4 In(III)-catalyzed cyclization/intermolecular hydrofunctionalization reactions using deuterated methanol-d₄ and 1,6-enyne 1-d₁.

According to our previous experimental and computational studies on indium(III)-catalyzed alkyne hydrofunctionalization, and 1,6-enyne cycloisomerization reactions,^13b we postulate a stepwise reaction mechanism initiated by the formation of an (η²-alkyne)-indium complex (I) that promotes the cyclization. Then, the enyne cyclization occurs with 5-exo-dig regioselectivity and anti-stereoselectivity, giving rise to a chiral zwitterionic transition state that involves an indium-stabilized homoallylic cationic species (II). Finally, the stereoselective nucleophilic addition affords an indium organometallic species (III) which undergoes a protodemetalation to give the corresponding cyclization product (Scheme 5).

Scheme 5 Mechanistic proposal.

Conclusions

In summary, herein we report the first tandem indium(III)-catalyzed 1,6-enyne cyclization and intermolecular nucleophilic addition for the synthesis of carbo- and heterocyclic structures. The reaction takes place under mild conditions using InI₃ (5 mol%) with good yields. Remarkably, indium(III) catalysis exhibits high chemoselectivity, enabling the incorporation of a variety of carbon, oxygen and nitrogen nucleophiles such as alcohols, water, carboxylic acids, arenes and azides, allowing the formation of C–C, C–O and C–N bonds in a wide number of functionalized carbo- and heterocyclic compounds. Furthermore, the synthetic transformation is highly regioselective (5-exo-dig) and stereoselective, proving the synthetic potential of indium(III) catalysis and opening the possibility of developing novel applications in organic synthesis and enantioselective transformations using other 1,n-enynes.

Author contributions

J. P. S. conceived the project and wrote the manuscript with contributions of all authors. R. P.-G., D. F.-I., and L. A.-M. performed the experimental work. M. M. M. and J. P. S. supervised the experimental work. All authors have given approval to the final version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information: experimental procedures and copies of the NMR spectra for all compounds prepared. See DOI: https://doi.org/10.1039/d5qo01388g.

Acknowledgements

We are grateful to Ministerio de Ciencia, Innovación y Universidades (Spain, PID2021-122335NB-I00, MCIN/AEI/10.13039/50110-0011033/FEDER, UE), Xunta de Galicia (GRC2022/039), and EDRF funds for financial and human support. R. P.-G. is grateful to Xunta de Galicia for a predoctoral fellowship.

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16. The (E)-3a-d₄ stereochemistry was assigned by ¹H NMR comparison according to the literature by the signal absence of the trans hydrogen (ref. 2c, see the SI for details).

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