Iron – Catalyzed Synthesis of Tetrahydronaphthalenes via 3,4-Dihydro-2H-pyran Intermediates.

Abstract

The development of an iron(III)-catalyzed synthetic strategy towards functionalized tetrahydronaphthalenes is described. This approach is characterized by its operational simplicity and is distinct from currently available procedures that rely on [4+2]-cycloadditions. Our strategy takes advantage of the divergent reactivity observed for simple aryl ketone precursors to gain exclusive access to tetrahydronaphthalene products (23 examples). Detailed mechanistic investigations identified pyrans as reactive intermediates that afford the desired tetrahydronaphthalenes in high yields upon iron(III)-catalyzed Friedel-Crafts alkylation.

Table of Contents Graphic.

Tetrahydronaphthalenes are key structural motifs in molecules of interest such as biologically active natural products¹ and pharmaceuticals,² as well as precursors to functional materials, including optoelectronics³ and organic semiconductors.⁴ Consequently, diverse areas of research rely on efficient and economical strategies to synthesize these important building blocks. Existing reports to access this structural motif often utilize Brønsted or Lewis acid-catalyzed [4+2]-cycloaddition reactions of o-alkynyl(oxo)-benzenes 5 with alkenes 6,⁵ or isochromene acetals 8 with vinyl boronates 9 (Fig. 1B).⁶ We herein present a mild and efficient strategy for the synthesis of tetrahydronaphthalenes 4 which was inspired by mechanistic insights obtained during our previous studies towards the synthesis of 3,4-dihydro-2H-pyrans 2 from aryl ketones 1 bearing α-carbonyl substituents.⁷ The corresponding α-arylated analogs of 1 exhibit divergent reactivity upon Brønsted or Lewis acid-catalysis resulting in either the preferential formation of pyrans 3 or the exclusive formation of tetrahydronaphthalenes 4 depending on the choice of activation (Fig. 1A). Divergent reactivity of the same substrate upon Lewis acid or Brønsted acid catalysis has recently been recognized as an attractive strategy to rapidly access molecular diversity.⁸ Subsequent mechanistic investigations aimed at the optimization of this transformation identified pyrans 3 as reactive intermediates which undergo FeCl₃-catalyzed⁹ Friedel-Crafts alkylation resulting in the exclusive formation of tetrahydronaphthalenes 4 in high yields. This strategy described herein provides a mild reaction protocol to access functionalized tetrahydronaphthalenes relying on iron as an environmentally benign metal catalyst and complements current synthetic approaches.

Figure 1.

A Divergent reactivity between Brønsted or Lewis acids. B Literature procedures for the formation of tetrahydronaphthalenes based on [4+2]-cycloadditions.

Following the discovery of divergent reactivity utilizing FeCl₃, we then investigated the suitability of other Lewis acids. When aryl ketone 11 was converted using catalytic amounts of Fe(OTf)₃, the corresponding tetrahydronaphthalene 12 was obtained in 23% yield with full conversion of the substrate (entry 1, Table 1). The use of Bi(OTf)₃¹⁰ resulted in increased yields of 48% while catalytic quantities of GaCl₃ further improved the yield of 12 to 58% (entries 2 and 3, Table 1). Both, SnCl₄ and BF₃·Et₂O resulted in the formation of tetrahydronaphthalene 12 in comparable yields of 87% while AlCl₃, a more potent Lewis acid, formed 12 in diminished yields of 73% (entries 4–6, Table 1). Catalytic amounts of FeCl₃ proved superior and gave rise to the desired tetrahydronaphthalene in 96% yield in an overall shorter reaction time of 8 hours (entry 7). Conducting the reaction with decreased catalyst loadings of 5 mol % FeCl₃ led to the formation of tetrahydronaphthalene 12 in 82% yield, albeit requiring longer reaction times of 24 hours (entry 8). In comparison, higher catalyst loadings of 20 mol % FeCl₃ resulted in decreased yields of 12 in 61% after 4 hours (entry 9). Furthermore, the evaluation of various solvents with FeCl₃ provided diminished reactivity, as dichloromethane, toluene and nitromethane resulted in 68%, 83% and 86% yield, respectively (entries 10–12, Table 1). Overall, 10 mol % of FeCl₃ in dichloroethane provided optimal reaction conditions. Importantly, orthogonal reactivity of aryl ketone 11 was observed upon treatment with 10 mol %, 100 mol %, and 500 mol % HCl, which resulted in the exclusive formation of the corresponding pyran product (3, Fig. 1A) (entries 13–15). The optimized reaction conditions for the synthesis of tetrahydronaphthalenes proved applicable to a variety of electronically differentiated aryl ketone substrates (Scheme 1). Electron-deficient aryl ketones incorporating nitro, halogen and nitrile functionalities were converted to the corresponding products 17–18, 21–22 in yields up to 96% (Scheme 1). In comparison, electron-neutral substrates bearing phenyl (12)- and biphenyl (15)- groups performed equally well and formed the desired products in yields up to 96% (Scheme 1). Additionally, electron-rich aryl ketones bearing methoxy, hydroxyl and acetate substittion were tolerated under the optimized reaction conditions and gave rise to the corresponding tetrahydronaphthalenes 25–26, 33 in up to 66% yield (Scheme 1). Thiophene and furan containing substrates proved viable and resulted in the formation of the desired products 19 and 23 in 64% and 56% yield, respectively. Cinnamyl-derived aryl ketones were also identified as suitable substrates for this transformation, tolerating a wide range of electron-rich and electron-deficient substituents in up to 99% yield (16, 20, 28–29, 24, Scheme 1). Importantly, aryl ketones bearing bromine or triflate substituents, which would enable subsequent functionalization via cross-coupling reactions, led to the desired tetrahydronaphthalene products in excellent yields of up to 98% (13 and 14, Scheme 1). Furthermore, the corresponding tetrahydronaphthalene products such as 16 undergo facile oxidation to the polyaromatic scaffold 35 in 82% yield upon treatment with DDQ (Fig. 2). Notably, this sequence provides an alternative synthetic strategy to current approaches towards functionalized naphthalenes 35 which often rely on gold-catalyzed benzannulation reactions of o-alkynyl(oxo)-benzenes 5.¹¹

Table 1.

Reaction optimization for the Lewis acid-catalyzed formation of tetrahydronaphthalene 12.

entry	Lewis acid	solvent	time (h)	yield(%)a	conversion (%)a
1	Fe(OTf)3	DCE	24	23	99
2	Bi(OTf)3	DCE	24	48	99
3	GaCl3	DCE	24	58	99
4	SnCl4	DCE	24	87	99
5	BF3.OEt2	DCE	24	87	99
6	AICI3	DCE	24	73	99
7	FeCl3	DCE	8	96b	99
8	FeCl3(5 mol %)	DCE	24	82	99
9	FeCl3(20 mol %)	DCE	4	61	99
10	FeCl3	DCM	4	68	99
11	FeCl3	PhMe	4	83	99
12	FeCl3	NO2Me	4	86	99
13c	HCI	DCE	24	0	17
14d	HCI (100 mol %)	DCE	24	0	20
15e	HCI (500 mol%)	DCE	24	0	68

^aPercent yield and percent conversion determined by ¹H-NMR using dimethyl terephthalate as an internal standard.

^bIsolated yield.

^c4% (24% brsm) pyran 3 observed.

^d20% (100% brsm) pyran 3 observed.

^e35% (52% brsm) pyran 3 observed.

^fAll reactions were performed using 0.113 – 0.189 mmol of aryl ketone.

Scheme 1.

Substrate scope of aryl and alkyl ketones.

Figure 2.

Oxidation of tetrahydronaphthalene 16 to give rise to functionalized naphthalene 35.

Subsequent studies focused on the elucidation of the reaction mechanism. During our evaluation of various Lewis acids, we observed the formation of a new compound after short reaction times. However, prolonged reaction times led to the isolation of the corresponding tetrahydronaphthalenes as the sole products suggesting the intermediacy of this compound in the reaction. Subsequent efforts focused on the isolation of thisreactive intermediate, which was later identified as the corresponding pyran 36. To validate this result, pyran 36 was prepared independently and subjected to the optimized reaction conditions (Fig. 3). After one hour, a mixture of aryl ketone 11 and tetrahydronaphthalene 12 was observed in a 2:1 ratio, respectively, suggesting that the formation of pyran 36 is reversible under Lewis acid catalysis. This hypothesis was further validated when the reaction was quenched after five hours, resulting in the formation of tetrahydronaphthalene 12 in 83% yield as the exclusive reaction product. Subsequent NMR experiments provided additional support for the formation of pyran 36 as a reactive intermediate (Fig. 4). The distribution of starting material 11, pyran 36, and tetrahydronaphthalene product 12 was monitored at different time points when ketone 11 was subjected to the optimized reaction conditions (Fig. 4A and 4B). Within the first two hours of the transformation, the majority of starting material 11 was consumed, and a high concentration of pyran 36 was observed. As the reaction progressed, the concentration of pyran 36 decreased as the concentration of tetrahydronaphthalene 12 increased. Figure 4C shows the changing composition of substrate 11, pyran 36 and product 12 in the reaction mixture after 0 minutes, 30 minutes, 6 hours, and 7 hours. Based on these mechanistic insights, we propose the following mechanism for the synthesis of tetrahydronaphthalenes (Fig. 5). Activation of aryl ketone 37 upon coordination of the Lewis acid leads to initial enolization of the carbonyl to provide 38, which can subsequently protonate the alkene subunit to form carbocation 39. The resulting carbocation 39 can either be trapped with the oxygen functionality of the iron-enolate 39 to result in pyran 40 or undergo Friedel-Crafts alkylation with the pendant aromatic moiety to from carbocation 41. Our experimental observations suggest that under Lewis acidic conditions pyran 40 forms initially. However, the reversibility of this step ultimately leads to the formation of tetrahydronaphthalene 42 following Friedel-crafts alkylation and rearomatization. In comparison Brønsted acid catalysis does not mediate the desired reaction pathway and provides pyrans 40 as products.

Figure 3.

Evidence for intermediacy of 36.

Figure 4.

A Monitoring conversion of aryl ketone 11 to product 12, via intermediate 36. B Distribution of 11, 12 and 36 as determined by percent yield using ¹H-NMR with dimethyl terephthalate as an internal standard. C Relevant sections of the ¹H-NMR spectra after 0 minutes, 30 minutes, 6 hours, and 7 hours.

Figure 5.

Mechanistic hypothesis for the FeCl₃-catalyzed formation of tetrahydronaphthalenes.

In summary, we have developed a mild and catalytic method for the synthesis of tetrahydronaphthalenes bearing a variety of electronically distinct substituents. Mechanistic investigations suggest the role of intermediate 3,4-dihydro-2H-pyrans in the FeCl₃-catalyzed synthesis of tetrahydronaphthalenes. This transformation illustrates the ability of aryl ketones to be selectively converted into 3,4-dihydro-2H-pyran or tetrahydronaphthalene products by the use of either a Brønsted or Lewis acid catalyst.