Iron(III) halide or iodine-promoted synthesis of 3-haloindene derivatives from o-alkynylarene chalcones

Abstract

o-Alkynylarene chalcones, when treated with ferric halides/iodine, undergo cyclization to give synthetically important 3-haloindene derivatives in good yields. The reactions proceed through Lewis acid-promoted intramolecular nucleophilic addition of the alkyne unit to the enone moiety followed by halide capture of the resulting vinyl carbocation intermediate. The reactions are operationally simple, require only inexpensive and environmentally friendly reagents and are applicable to a range of substrates.

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The presence of an indene core in many natural products,¹ medicinally active compounds,² synthetic intermediates,³ functional materials⁴ and organometallic catalysts⁵ has driven the development of numerous methods for the synthesis of indene derivatives.⁶ However, only a limited number of reports are available for the synthesis of haloindene derivatives despite the fact that the presence of halogen in their structure would allow further synthetic elaboration via palladium chemistry. In recent years, boron trifluoride-catalyzed Friedel–Crafts cyclization of iodinated allylic alcohols,⁷ iodocyclization of o-(alkynyl)arenemalonates,⁸ halocyclization of o-(alkynyl)styrenes⁹ and Pd-catalyzed cyclization of o-alkynylbenzylidene ketones/esters^10,11 have been reported for the synthesis of haloindenes. In the latter reports, Wu et al., have used Pd(OAc)₂/CuX₂ (X = Cl, Br) for the cyclization of o-alkynylbenzylidene ketones/esters to obtain 3-chloro- and 3-bromo-1-methyleneindenes (Scheme 1, eqn 1)¹⁰ and Lu et al., have used Pd(OAc)₂/LiX (X = Cl, Br) to get 3-chloro- and 3-bromo-1H-indene derivatives (Scheme 1, eqn 2).¹¹ We herein report the FeX₃ (X = Cl, Br) or iodine-mediated cyclization of o-alkynylarene ketones (mainly chalcones) 1 for the facile synthesis of 3-chloro-, 3-bromo- and 3-iodo-1H-indene derivatives 2/3/4 (Scheme 1, eqn 3).

Scheme 1 Synthesis of indenes from o-alkynylbenzylidene ketones or esters.

Recently, iron(III) halides¹² and iodine¹³ have emerged as more economical and greener Lewis acids for various organic transformations. It may also be noted that o-alkynylarene chalcones are gaining popularity as versatile synthetic building blocks and have been used for access to various compounds such as 1,2-dihydroisoquinolin-3(4H)-imines,¹⁴ tetra-hydroindeno[2,1-b]pyrroles,¹⁵ benzo[b]fluorenols,¹⁶ benzo[g]indazoles and naphtho[2,1-d]isoxazoles.¹⁷

The effectiveness of iron(III) halides in catalyzing alkyne–carbonyl metathesis¹⁸ and promoting Prins-type cyclization of functionalized alkynes¹⁹ prompted us to investigate their action on o-alkynylarene chalcones as these compounds contain alkyne and enone functional groups. Accordingly, we chose the chalcone 1a as a model substrate and treated this with anhydrous FeCl₃ (1 equiv.) in dichloromethane (Table 1, entry 1). The starting material did not undergo any change at room temperature nor under reflux conditions. Next, we changed the solvent to 1,2-dichloroethane (1,2-DCE). Even though the reaction did not take place at room temperature, under reflux conditions, 3-chloroindene 2a was produced in 86% isolated yield (entry 2). When the amount of FeCl₃ was reduced to 50 mol%, the yield dropped to 42%, indicating that the chloride was incorporated in the product from the reagent (entry 3). On the other hand, when 1.5 equiv. of FeCl₃ was employed, the yield dropped slightly to 77% due to the formation of impurities (entry 4). The reaction also worked with FeCl₃·6H₂O, but the yield was low (71%) (entry 5). When other Lewis acids such as AlCl₃, InCl₃ and TiCl₄ were employed, the product was obtained in lower yields (entries 6–8). Switching the solvent to acetonitrile also lowered the yield (entry 9) while the reaction did not work in THF (entry 10).

Table 1 Optimization of reaction conditions

S. no.	Reagents (equiv.) and conditions	Yield of 2a^a (%)
a Isolated yield.b No reaction.
1	FeCl3 (1), CH2Cl2, rt/reflux, 24 h	NR^b
2	FeCl3 (1), 1,2-DCE, reflux, 2 h	86
3	FeCl3 (0.5), 1,2-DCE, reflux, 24 h	42
4	FeCl3 (1.5), 1,2-DCE, reflux, 2 h	77
5	FeCl3·3H2O (1), 1,2-DCE, reflux, 2 h	71
6	AlCl3 (1), 1,2-DCE, reflux, 24 h	52
7	InCl3 (1), 1,2-DCE, reflux, 24 h	52
8	TiCl4 (1), 1,2-DCE, reflux, 24 h	48
9	FeCl3 (1), CH3CN, reflux, 24 h	60
10	FeCl3 (1), THF, reflux, 24 h	NR^b

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Since the reagent supplied chloride in the above reaction, we envisaged that by using FeBr₃ in the reaction, it would be possible to get the corresponding 3-bromoindene. As expected, when 1a was treated with FeBr₃, it afforded 3-bromoindene 3a in 77% yield. Our further work revealed that I₂ was also capable of promoting the reaction, and it furnished 3-iodoindene 4a in 90% yield (Scheme 2).

Scheme 2 Synthesis of 3-bromoindene 3a and 3-iodoindene 4a from 1a.

With the availability of suitable reaction conditions for preparing chloro, bromo- and iodoindenes, we next focused our attention on investigating the scope of the reactions for various o-alkynylarene chalcones having different substitution patterns, and the results are summarized in Table 2. When electron releasing methyl and methoxy groups were placed on the aromatic ring (R⁴) attached to the enone unit, the reactions proceeded well and the respective haloindenes 2b, 2c, 3b, 3c, 4b and 4c were produced in 70–85% yields. The reactions also tolerated a 4-bromophenyl ring in the position and furnished the haloindenes 2d, 3d and 4d in 80–83% yields. However, for 4-nitrophenyl ring, the reactions failed to give the respective haloindenes 2e, 3e and 4e, possibly due to the coordination of the Lewis acids to the nitro group. Interestingly, when the aryl ring in the position was replaced by an alkyl group (methyl), the reactions took place and furnished the haloindenes 2f, 3f and 4f, though the yields are slightly lower. We also replaced the phenyl ring (R³) attached to the alkyne unit with 4-methylphenyl ring and aliphatic, n-butyl group. In both cases, the corresponding haloindenes 2g, 2h, 3g, 3h, 4g and 4h were obtained in good yields. Finally, we changed the substituents R¹ and R² on the main aryl ring of the chalcones. The reactions were successful when the two methoxy groups were replaced by a methylenedioxy unit and also when there was a single methoxy group on the ring to give haloindenes 2i, 2j, 3i, 3j, 4i and 4j (the structure of 4i was unambiguously confirmed by X-ray crystallographic analysis,²⁰ Fig. 1). Even though the reaction worked for the o-alkynylarene chalcone having no methoxy substituent, the respective haloindenes 2k, 3k and 4k could not be isolated in pure form as they underwent decomposition during column purification.

Table 2 Synthesis of various 3-haloindenes from o-alkynylarene chalcones^a

a All yields are isolated products.b No reaction.c The product decomposed during purification.

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Fig. 1 X-ray structure of iodoindene 4i.

We propose a plausible mechanism depicted in Scheme 3 for the formation of 3-haloindenes 2–4 from o-alkynylarene chalcones 1.^21,11,18a The Lewis acid (Z–X, Z = FeCl₂, FeBr₂ or I and X = Cl, Br, I) coordinates to the oxygen atom of the enone unit of 1, which leads to the formation of the benzylic carbocation A. The ensuing intramolecular nucleophilic attack by the alkyne moiety generates the vinylic carbocation B, which readily captures a halide ion from another B to give 3-haloindene enolate C. Exposure to moisture (H₂O) converts the enolate into carbonyl to give 3-haloindene derivative 2, 3 or 4. The resemblance of the mechanism to that of the Prins cyclization is worth noting.^19b

Scheme 3 Plausible mechanism for the formation of 3-haloindenes.

To demonstrate the utility of the synthesized 3-haloindenes for further transformation via palladium chemistry, we performed a Suzuki coupling of the 3-iodoindene 4i with 4-methoxyphenylboronic acid in the presence of catalytic amounts of Pd(OAc)₂ and SPhos and two equiv. of K₃PO₄ in toluene under reflux conditions (Scheme 4).⁹ Pleasingly, the expected cross-coupling took place; however, the product underwent concomitant oxidation²² under the reaction conditions to yield the 1-methyleneindene derivative 5 in 76% yield.

Scheme 4 Synthetic application of 3-iodoindene 4i.

In summary, we have developed an efficient ferric halides/iodine-mediated procedure for the conversion of o-alkynylarene chalcones into 3-haloindene derivatives. The advantages of the method include the operational simplicity, use of economic and green reagents, reasonably wide substrate scope and formation of products in good yields. Further, the products are useful synthetic intermediates and could be subjected to further synthetic elaboration.

Acknowledgements

The authors thank the Council of Scientific and Industrial Research (CSIR) and Department of Science and Technology (DST), India for financial support; DST-FIST for instrumentation facilities at School of Chemistry, Bharathidasan University and Dr N. Sampath, Sastra University for X-ray structure determination.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1022843. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra14935a

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