Synthesis of Multisubstituted Indenes via Iron-Catalyzed Domino Reaction of Benzylic Compounds and Alkynes

Abstract

A novel approach to synthesizing multisubstituted indenes by iron-catalyzed domino reaction of benzylic compounds and alkynes under mild conditions was developed. This system could be applied to various available substrates in a one-step synthetic procedure in moderate to good yields.

Key words

indenes - iron catalysis - domino reaction - one-step procedure - annulation

The indene core is one of the most important cyclic motifs that are very common in natural products and biologically active compounds.[ ¹ ] In addition, it has tremendous applications in various research fields including material chemistry, analytical chemistry, and synthetic organic chemistry.[ ² ] Great progress has been made to successfully construct this motif, but traditional methods required expensive and difficult-to-prepare catalysts/reagents, tedious reaction procedures, moreover, it is difficult to directly introduce multifunctional groups into the indene core.[ ³ ] Recently, several new approaches[ ⁴ ] to generating indenes from the reaction between carbon–carbon triple bonds and benzyl cation intermediates that are obtained by the use of leaving groups have been developed (Scheme [1, ]A).

In recent years, the direct functionalization of benzylic C(sp³)–H bonds has attracted extensive attention in organic synthesis.[5] [6] [7] [8] For example, Shi and others[ ⁵ ] have reported the cross-dehydrogenative coupling (CDC) between benzylic C–H bonds and sp³, sp², or sp C–H bonds. Direct benzylic C–H amination through various catalytic systems have also been developed.[ ⁶ ] Additionally, the Jiao group[ ⁷ ] demonstrated an iron-catalyzed transformation of benzylic compounds into corresponding amide through C–H and C–C bond cleavage. Among these reactions, iron is a particularly attractive catalyst because of its sustainability, easy availability, low price, and environmentally friendly characteristics.[ ⁹ ] Despite the significant progress that has been achieved in this area, the cyclization reaction is still a relatively unexplored field. Owing to the importance of indene derivatives and the lack of successful direct annulations from benzylic compounds without leaving groups, we initially envisioned a novel and efficient way of synthesizing multisubstituted indenes by in situ generated benzyl bromides as benzyl cation precursors in an iron-catalyzed, one-step synthetic procedure (Scheme [1, ]B).

Scheme 1 Synthesis of indene derivatives

At the outset of our study, diphenylacetylene (1a) and diphenylmethane (2a) were chosen as model substrates to optimize the reaction conditions (Table [1]). Compounds 3aa and 4aa were obtained in 10% and 56% yields, respectively, with FeCl₂ (10 mol%) as the catalyst and DDQ (2.0 equiv) as the oxidant in DCE at 80 °C (Table [1], entry1). The yield of 3aa increased to 66% when NBS was used as the oxidant, while other oxidants such as NCS, TBHP, and Cu(OAc)₂ showed no effect on the promotion of this domino reaction (Table [1], entries 2–5). Subsequently, a series of solvents (toluene, acetonitrile, nitromethane, and tetrahydrofuran) were also evaluated but they showed disappointing results (Table [1], entries 6–9). Furthermore, we investigated the reaction using other iron, copper, and zinc salts as catalyst, but no better results were obtained (Table [1], entries 10–14). It is noteworthy that the amount of NBS had a significant effect on this reaction. Both 1.5 equivalents and 3.0 equivalents of NBS offered the desired product 3aa in a low yield; 2.2 equivalents of NBS were the most effective and resulted in 75% yield (Table [1], entries 15–17). In addition, the yield was found to decrease with the temperature changed to 60 °C or 120 °C (Table [1], entries 18 and 19), and only a trace amount of product was observed in the absence of NBS or FeCl₂.

Table 1 Optimization of the Reaction Conditions^a

Entry	Oxidant (equiv)	Catalyst	Solvent	Temp (°C)	Yield of 3aa (%)	Yield of 4aa (%)
1	DDQ (2.0)	FeCl2	DCE	80	10	56
2	NBS (2.0)	FeCl2	DCE	80	66	12
3	NCS (2.0)	FeCl2	DCE	80	trace	0
4	TBHP (2.0)	FeCl2	DCE	80	trace	0
5	Cu(OAc)2 (2.0)	FeCl2	DCE	80	trace	0
6	NBS (2.0)	FeCl2	PhMe	80	15	42
7	NBS (2.0)	FeCl2	MeCN	80	0	0
8	NBS (2.0)	FeCl2	MeNO2	80	0	0
9	NBS (2.0)	FeCl2	THF	80	0	0
10	NBS (2.0)	FeBr2	DCE	80	43	0
11	NBS (2.0)	FeCl3	DCE	80	44	15
12	NBS (2.0)	Fe(acac)3	DCE	80	trace	20
13	NBS (2.0)	CuCl2	DCE	80	trace	0
14	NBS (2.0)	ZnCl2	DCE	80	trace	0
15	NBS (1.5)	FeCl2	DCE	80	56	20
16	NBS (2.2)	FeCl2	DCE	80	75	0
17	NBS (3.0)	FeCl2	DCE	80	47	0
18	NBS (2.2)	FeCl2	DCE	60	67	0
19	NBS (2.2)	FeCl2	DCE	120	60	0

^a Reaction conditions: 1a (0.25 mmol), 2a (1.25 mmol), catalyst (0.025 mmol), solvent (2 mL), under N₂, 12 h.

Under the optimized reaction conditions, a series of substituted substrates was investigated to establish the scope and limitations of this process (Table [2]). The results showed that substrates with various weakly electron-donating and electron-withdrawing functional groups on either alkynes or benzylic compounds gave the corresponding indenes in moderate to good yields, and other strongly electron-donating and electron-withdrawing substituents gave no desired products probably because of strong electronic effect (Table [2], entries 7, 8, and 17). The corresponding product 3da was obtained in good yield when the substrate with an ortho-substituted aryl group was employed (Table [2], entry 4). Moreover, substrates with different substituents on R¹ and R² gave a mixture of regioisomers; due to electronic effects, the ratio of isomers varied from 3.7:1 to 1.3:1 (Table [2], entries 2, 4, 5; see also the Supporting Information).[4a] [b] The aliphatic alkynes gave lower but still acceptable yields with perfect regioselectivity (Table [2], entries 9 and 10).[ ^4a,b ] When unsymmetric diphenylmethanes were employed, exclusive regioselectivity of indenes were observed except for 3ab and 3ad (Table [2], entries 11, 13–19; see also the Supporting Information). Confirmed by ¹H NMR and ¹³C NMR analyses of intermediate product 4ae, we assumed the favorable isomer would be 3ae.[ ^4b ] A low yield was obtained when the bis[4-(tert-butyl)phenyl]methane was used, probably because of the steric effects of the tert-butyl substituent (Table [2], entry 12). Besides diarylmethanes, simple benzylic substrates such as ethyl benzene also worked smoothly and gave a mixture of diastereomers (1:1 ratio) in 56% yield (Table [2], entry 16).

Interestingly, it was found that substrates with a para-methoxy group on the aryl ring could react smoothly by using DDQ as oxidant (Table [3], entry 1). Good yield was still achieved when the bis[4-(tert-butyl)phenyl]methane was used (Table [3], entry 2).

Table 2 Synthesis of Indenes Derivatives from Alkynes and Benzylic Compounds^a

Entry	1 R1, R2	2 Ar, R3	NBS (equiv)	Yield of 3 (%)
1	1a Ph, Ph	2a Ph, Ph	2.2	3aa 75
2	1b Ph, 4-MeC6H4	2a Ph, Ph	1.9	3ba/3ba′ (1:3.7) 72
3	1c 4-MeC6H4, 4-MeC6H4	2a Ph, Ph	1.6	3ca 53
4	1d Ph, 2-MeC6H4	2a Ph, Ph	1.8	3da/3da′ (1:1.3) 69
5	1e Ph, 4-ClC6H4	2a Ph, Ph	2.2	3ea/3ea′ (1:1.3) 83
6	1f 4-ClC6H4, 4-ClC6H4	2a Ph, Ph	2.5	3fa 74
7	1g Ph, 4-O2NC6H4	2a Ph, Ph	2.2	3ga 0
8	1h Ph, 4-MeOC6H4	2a Ph, Ph	2.2	3ha 0
9	1i Ph, Bu	2a Ph, Ph	3.0	3ia 55
10	1j n-Pr, n-Pr	2a Ph, Ph	2.2	3ja 42
11	1a Ph, Ph	2b Ph, 4-MeC6H4	2.2	3ab (Ar = Ph)/3ab′ (Ar = 4-MeC6H4) (1:1) 62
12	1a Ph, Ph	2c 4-t-BuC6H4, 4-t-BuC6H4	2.6	3ac 48c
13	1a Ph, Ph	2d Ph, 4-FC6H4	2.6	3ad (Ar = Ph)/3ad′ (Ar = 4-FC6H4) (2:1) 58
14	1a Ph, Ph	2e Ph, 4-ClC6H4	2.4	3ae 57
15	1a Ph, Ph	2f Ph, 4-F3CC6H4	3.0	3af 63c
16	1a Ph, Ph	2g Ph, Me	2.2	3ag 56d
17	1a Ph, Ph	2h Ph, 4-MeOC6H4	2.2	3ah 0
18	1f 4-ClC6H4, 4-ClC6H4	2e Ph, 4-ClC6H4	2.8	3fe 72
19	1f 4-ClC6H4, 4-ClC6H4	2f Ph, 4-F3CC6H4	3.0	3ff 45b

^a Reaction conditions: 1 (0.25 mmol), 2 (1.25 mmol), FeCl₂ (0.025 mmol), DCE (2 mL), 80 °C, 10 h, under N₂.

^b At 100 °C, 24 h.

^c At 100 °C.

^d At 60 °C.

To gain an insight into the mechanism of the above-mentioned process, the following control experiments were performed. As shown in Scheme [2, ](bromomethylene)dibenzene A was obtained via reaction of diphenylmethane (2a) with NBS in DCE under optimized conditions (Scheme [2, ]A), and then diphenylacetylene (1a) and FeCl₂ were added to the reaction mixture (Scheme [2, ]B), and 3aa was obtained in 74% yield.

Table 3 Synthesis of Indene Derivatives Using DDQ as Oxidant^a

Entry	1 R1, R2	2 Ar, R3	Yield of 4 (%)
1	1h Ph, 4-MeOC6H4	2a Ph, Ph	4ha 55
2	1a Ph, Ph	2c 4-t-BuC6H4, 4-t-BuC6H4	4ac 65

^a Reaction conditions: 1 (0.25 mmol), 2 (1.25 mmol), FeCl₂ (0.025 mmol), DDQ (0.625 mmol), DCE (2 mL), 100 °C, 10 h, under N₂.

On the basis of the above results, a tentative reaction mechanism is illustrated in Scheme [2] (C). Treatment of diphenylmethane (2a) with NBS produces (bromomethylene)dibenzene A. The reaction of iron salt on A can lead to benzylic cation, which regioselectively attacks 1a resulting in the formation of vinyl cation C. Then C undergoes cyclization and subsequent aromatization to provide 4aa.[4a] [b] [10] Finally, 4aa and a second A react to afford the desired product 3aa.[ ¹¹ ]

Scheme 2 A tentative reaction mechanism

In summary, we have developed a novel iron-catalyzed direct cyclization for the synthesis of multisubstituted indenes with benzylic compounds and alkynes in moderate to good yields. This system could be applied to various available substrates in a one-step synthetic procedure. We believe that this is one of the simplest and most straightforward methods available for the synthesis of indenes to date.

Acknowledgment

We are grateful to the project sponsored by the Project of National Science Foundation of P. R. of China (No. J11003307).

• References and Notes

• 1a Nugiel DA, Etzkom A.-M, Vidwans A, Benfield PA, Boisclair M, Burton CR, Cox S, Czerniak PM, Doleniak D, Seitz SP. J. Med. Chem. 2001; 44: 1334
• 1b Frédérick R, Dumont W, Ooms F, Aschenbach L, van der Schyf CJ, Castagnoli N, Wouters J, Krief A. J. Med. Chem. 2006; 49: 3743
• 1c Heintzelman GR, Averill KM, Dodd JH, Demarest KT, Tang Y, Jackson PF. WO 2003088963, 2003
• 1d Safak C, Simsek R, Altas Y, Boydag S, Erol K. Boll. Chim. Farm. 1997; 136: 665
• 2a Anstead GM, Wilson SR, Katzenellenbogen JA. J. Med. Chem. 1989; 32: 2163
• 2b Wang B. Coord. Chem. Rev. 2006; 250: 242
• 2c Xi Q, Zhang W, Zhang X. Synlett 2006; 945
• 2d Barberá J, Rakitin OA, Ros MB, Torroba T. Angew. Chem. Int. Ed. 1998; 37: 296
• 2e Banide EV, O’Connor C, Fortune N, Ortin Y, Milosevic S, Müller-Bunz H, McGlinchey MJ. Org. Biomol. Chem. 2010; 8: 3997
• 2f Zargarian D. Coord. Chem. Rev. 2002; 233-234: 157
• 2g Morinaka K, Ubukata T, Yokoyama Y. Org. Lett. 2009; 11: 3890
• 2h Yang J, Lakshmikantham MV, Cava MP, Lorcy D, Bethelot JR. J. Org. Chem. 2000; 65: 6739
• 2i Alt HG, Köppl A. Chem. Rev. 2000; 100: 1205
• 3a Zhou X, Zhang H, Xie X, Li Y. J. Org. Chem. 2008; 73: 3958
• 3b Marion N, Díez-González S, de Frémont P, Noble AR, Nolan SP. Angew. Chem. Int. Ed. 2006; 45: 3647
• 3c Kurouchi H, Sugimoto H, Otani Y, Ohwada T. J. Am. Chem. Soc. 2010; 132: 807
• 3d Womack GB, Angeles JG, Fanelli VE, Heyer CA. J. Org. Chem. 2007; 72: 7046
• 3e Zhu Z.-B, Shi M. Chem. Eur. J. 2008; 14: 10219
• 3f Zhang X.-M, Tu Y.-Q, Jiang Y.-J, Zhang Y.-Q, Fan C.-A, Zhang F.-M. Chem. Commun. 2009; 4726
• 3g Li C, Zeng Y, Wang J. Tetrahedron Lett. 2009; 50: 295
• 3h Khan ZA, Wirth T. Org. Lett. 2009; 11: 229
• 3i Zhang D, Yum EK, Liu Z, Larock RC. Org. Lett. 2005; 7: 4963
• 3j Bi H.-P, Liu X.-Y, Gou F.-R, Guo L.-N, Duan X.-H, Liang Y.-M. Org. Lett. 2007; 9: 3527
• 3k Bryan CS, Lautens M. Org. Lett. 2010; 12: 2754
• 3l Rayabarapu DK, Cheng C.-H. Chem. Commun. 2002; 9: 942
• 3m Deng R, Sun L, Li Z. Org. Lett. 2007; 9: 5207
• 3n Kuninobu Y, Kawata A, Takai K. J. Am. Chem. Soc. 2005; 127: 13498
• 3o Miyamoto M, Harada Y, Tobisu M, Chatani N. Org. Lett. 2008; 10: 2975
• 3p Kuninobu Y, Tokunaga Y, Kawata A, Takai K. J. Am. Chem. Soc. 2006; 128: 202
• 3q Chang K.-J, Rayabarapu DK, Cheng C.-H. J. Org. Chem. 2004; 69: 4781
• 4a Bu X, Hong J, Zhou X. Adv. Synth. Catal. 2011; 353: 2111
• 4b Liu C.-R, Yang F.-L, Jin Y.-Z, Ma X.-T, Cheng D.-J, Li N, Tian S.-K. Org. Lett. 2010; 12: 3832
• 4c Li H, Li W, Liu W, He Z, Li Z. Angew. Chem. Int. Ed. 2011; 50: 2975
• 5a Rong Y, Li R, Lu W. Organometallics 2007; 26: 4376
• 5b Li Z, Cao L, Li C.-J. Angew. Chem. Int. Ed. 2007; 46: 6505
• 5c Li Y.-Z, Li B.-J, Lu X.-Y, Lin S, Shi Z.-J. Angew. Chem. Int. Ed. 2009; 48: 3817
• 5d Correia CA, Li C.-J. Adv. Synth. Catal. 2010; 352: 1446
• 6a Liu X, Zhang Y, Wang L, Fu H, Jiang Y, Zhao Y. J. Org. Chem. 2008; 73: 6207
• 6b Pelletier G, Powell DA. Org. Lett. 2006; 8: 6031
• 6c Powell DA, Fan H. J. Org. Chem. 2010; 75: 2726
• 6d Ye Y.-H, Zhang J, Wang G, Chen S.-Y, Yu XQ. Tetrahedron 2011; 67: 4649
• 6e Wang Z, Zhang Y, Fu H, Jiang Y, Zhao Y. Org. Lett. 2008; 10: 1863
• 6f Xia Q, Chen W, Qiu H. J. Org. Chem. 2011; 76: 7577
• 7 Qin C, Zhou W, Chen F, Ou Y, Jiao N. Angew. Chem. Int. Ed. 2011; 50: 12595
• 8a Rybtchinski B, Milstein D. Angew. Chem. Int. Ed. 1999; 38: 870
• 8b Li Z, Li C.-J. J. Am. Chem. Soc. 2005; 127: 6968
• 8c Coperet C. Chem. Rev. 2010; 110: 656
• 8d Sun C.-L, Li B.-J, Shi Z.-J. Chem. Rev. 2011; 111: 1293
• 8e Ramesh D, Ramulu U, Rajaram S, Prabhakar P, Venkateswarlu Y. Tetrahedron Lett. 2010; 51: 4898
• 8f Li Z, Yu R, Li H. Angew. Chem. Int. Ed. 2008; 47: 7497
• 8g Li C.-J. Acc. Chem. Res. 2009; 42: 335
• 9a Bolm C, Legros J, Le Paih J, Zani L. Chem. Rev. 2004; 104: 6217
• 9b Bolm C. Nat. Chem. 2009; 1: 420
• 9c Enthaler S, Junge K, Beller M. Angew. Chem. Int. Ed. 2008; 47: 3317
• 9d Fürstner A, Leitner A, Méndez M, Krause H. J. Am. Chem. Soc. 2002; 124: 13856
• 9e Sherry BD, Fürstner A. Acc. Chem. Res. 2008; 41: 1500
• 9f Bauer EB. Curr. Org. Chem. 2008; 12: 1341
• 10a Stang PJ, Anderson AG. J. Am. Chem. Soc. 1978; 100: 1520
• 10b Viswanathan GS, Wang MW, Li CJ. Angew. Chem. Int. Ed. 2002; 41: 2138
• 10c Stang PJ, Rappoport Z, Hanack M, Subramanian LR. Vinyl Cations. Academic Press; New York: 1979
• 11 General Procedure for the Iron-Catalyzed Domino Reaction – Synthesis of 6-Benzhydryl-1,2,3-triphenyl-1H-indene (3aa) Diphenylacetylene 1a (44.5 mg, 0.25 mmol), FeCl₂ (3.1 mg, 10 mmol%), and NBS (97.9 mg, 0.55 mmol) were added to a flask with a magnetic stirring bar. The tube was evacuated and refilled with N₂, and then diphenylmethane (2a, 210 μL, 1.25 mmol) and DCE (2 mL) was added. The resulting mixture was stirred at 80 °C for 10 h. After cooling to r.t., the mixture was diluted with EtOAc and filtered. The filtrate was removed under reduced pressure to get the crude product, which was further purified by silica gel chromatography (PE as eluent) to give product 3aa (75% yield); white solid; mp 155–157 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.40–7.28 (m, 5 H), 7.22–7.13 (m, 8 H), 7.10–6.98 (m, 14 H), 6.98–6.94 (m, 1 H), 5.50 (s, 1 H), 5.03 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 148.4, 145.5, 144.1, 144.0, 143.4, 141.6, 140.4, 139.7, 135.5, 129.4, 129.2, 129.1, 128.6, 128.5, 128.2, 128.1, 127.8, 127.4, 126.5, 126.1, 125.3, 120.1, 57.9, 56.8.