Enantioselective synthesis of 4,5,6,7-tetrahydroindoles via olefin cross-metathesis/intramolecular Friedel–Crafts alkylation reaction of pyrroles

Abstract

A sequential catalysis involving olefin cross-metathesis/asymmetric intramolecular Friedel–Crafts alkylation of pyrrole derivatives has been developed. A variety of enantioenriched 4,5,6,7-tetrahydroindoles were obtained in good yields and enantioselectivity by combining a Zhan-1B catalyst with a chiral phosphoric acid.

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Over the past several years, sequential catalysis consisting of a transition-metal catalyst and a chiral phosphoric acid (CPA) has been one of the most effective synthetic approaches for the construction of complex molecules with diverse functional groups in a single operation.^1–3 In addition, this system also features the utilization of readily available starting materials, minimization of wastes and reduction of labor. Most notably, it could achieve novel and unprecedented transformations due to the synergistic effects within two catalytic processes, providing important chiral scaffolds which could not be obtained by employing either single catalyst alone. Therefore sequential catalysis has now become an intense research area in organic synthesis. In 2009, our group demonstrated a sequential catalysis involving Ru-catalyzed olefin cross-metathesis followed by a subsequent Brønsted acid catalyzed intramolecular Friedel–Crafts alkylation of indoles, providing a variety of enantioenriched and biologically active polycyclic indoles (Scheme 1, top).⁴ To the best of our knowledge, however, there is no example of a sequential reaction involving cross-metathesis and Friedel–Crafts alkylation based on pyrrole scaffold despite its frequent occurrence in biologically active natural products and pharmaceuticals.⁵ Compared with indoles, fewer asymmetric Friedel–Crafts alkylation reactions of pyrroles^6,7 were reported, likely due to the increased challenges on regio- and enantioselective control. With our continuing interest in sequential catalysis,^4,8 we envisioned that cross-metathesis and asymmetric Friedel–Crafts alkylation of pyrroles might be achieved by fine tune of the substrates and catalysts (Scheme 1, below). Herein we report such a sequential catalysis involving pyrrole substrates for the synthesis of enantioenriched tetrahydroindoles.⁹

Scheme 1 Cross-metathesis and asymmetric Friedel–Crafts alkylation of indoles and pyrroles.

We began our studies by examining chiral phosphoric acids with different substituents in the sequential reaction between pyrrole olefin 1a and phenyl vinyl ketone 2a. The reaction of 1a and 1.5 equivalents of phenyl enone 2a in the presence of 5 mol% chiral phosphoric acid (S)-4 and 5 mol% Hoveyda–Grubbs II in toluene at 60 °C all proceeded to completion within 1 hour to give the desired product in good yields (56–71%) and moderate to good enantioselectivity (18–62% ee). As summarized in Table 1, the substituent of the catalyst had a great influence on the enantioselectivity of the reaction. Chiral phosphoric acids 4c bearing 1-naphthyl groups and 4e bearing 4-biphenyl groups proved to be the most efficient catalysts in terms of reactivity and enantioselectivity, affording 3a in 56% yield, 62% ee and 71% yield, 60% ee respectively (Table 1, entries 3 and 5).

Table 1 Screening of chiral phosphoric acids^a

Entry	4, Ar	Yield^b (%)	ee^c (%)
a Reaction conditions: 1a (0.20 mmol), 2a (0.30 mmol), Hoveyda–Grubbs II (5 mol%) and (S)-4 (5 mol%) in toluene (2 mL) at 60 °C. b Isolated yield. c Determined by HPLC analysis.
1	4a, 2,4,6-(^iPr)3-C6H2	61	18
2	4b, SiPh3	65	20
3	4c, 1-naphthyl	56	62
4	4d, 2-naphthyl	64	19
5	4e, 4-biphenyl	71	60
6	4f, 4-NO2-C6H4	67	44
7	4g, 4-[3,5-(CF3)2-C6H3]-C6H4	66	50
8	4h, 9-anthryl	60	52
9	4i, 9-phenanthryl	59	55
10	4j, 3,5-(CF3)2-C6H3	61	29
11	4k, 2-isopropoxy-1-naphthyl	66	54

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Encouraged by these results, other reaction parameters such as reaction temperature, ruthenium catalysts and solvents were further investigated with (S)-4c as the optimal Brønsted acid. The results are summarized in Table 2. At a lower temperature, the reaction delivered the corresponding product with an increased ee value albeit slightly decreased yield (Table 2, entries 1–4). For example, when the reaction was performed at 40 °C, the ee value of the product could be increased to 72% (Table 2, entry 2). Notably, Zhan-1B could also provide product 3a in 70% ee with a slightly higher yield (54% yield) (Table 2, entry 5). Given its cheapness, Zhan-1B was used for further optimization of the reaction conditions. Among the molecular sieves with different sizes, the addition of 3 Å MS gave better results (Table 2, entry 6, 60% yield, 72% ee). Other solvents such as o-xylene, CH₂Cl₂, THF and ether all led to the formation of 3a in comparable yields but with decreased enantioselectivity (Table 2, entries 9–12, 66–72% yields and 32–54% ee). To our great delight, the amount of enone 2a could be further reduced to 1.2 equivalents without the erosion of yield and enantioselectivity (Table 2, entry 13, 60% yield, 72% ee). Thus the optimized conditions were obtained as the following: 5 mol% of (S)-4c, 5 mol% of Zhan-1B, 1.2 equivalents of enone 2, 3 Å MS as an additive in toluene at 40 °C.

Table 2 Optimization of the reaction conditions for the sequential reaction^a

Entry	[Ru]	Additive	Solvent	Temp (°C)	Time (h)	Yield^b (%)	ee^c (%)
a Reaction conditions: 1a (0.20 mmol), 2a (0.30 mmol), Ru catalyst (5 mol%), (S)-4c (5 mol%) and MS (100 mg) in solvent (2 mL). b Isolated yield. c Determined by HPLC analysis. d 0.24 mmol of 2a was used.
1	Hoveyda–Grubbs II	None	Toluene	60	1	56	62
2	Hoveyda–Grubbs II	None	Toluene	40	1	50	72
3	Hoveyda–Grubbs II	None	Toluene	rt	10	52	70
4	Hoveyda–Grubbs II	None	Toluene	0	10	25	68
5	Zhan-1B	None	Toluene	40	1	54	70
6	Zhan-1B	3 Å MS	Toluene	40	1	60	72
7	Zhan-1B	4 Å MS	Toluene	40	1	58	70
8	Zhan-1B	5 Å MS	Toluene	40	1	43	72
9	Zhan-1B	3 Å MS	CH2Cl2	40	1.5	66	50
10	Zhan-1B	3 Å MS	o-Xylene	40	1	67	44
11	Zhan-1B	3 Å MS	Et2O	40	3	66	54
12	Zhan-1B	3 Å MS	THF	40	1	72	32
13	Zhan-1B	3 Å MS	Toluene	40	1	60	72

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Under the above mentioned optimized reaction conditions, we then examined the substrate scope of this reaction. The results are summarized in Table 3. Besides phenyl enone, 2-naphthyl enone (2b) was also a suitable substrate, giving 3b in 44% yield and 67% ee. With N-Bn protected pyrrole olefin (2c) as a substrate, both enantioselectivity and yield were significantly increased (Table 3, 3c, 93% yield, 84% ee). When the phenyl group at the C5 position of pyrrole was replaced by methyl or benzoylethyl, the sequential reaction also occurred smoothly, affording the tetrahydroindole products in good yields and ee (3d: 56% yield, 84% ee; 3e: 88% yield, 80% ee). Interestingly, when pyrrole olefin without a substituent at the C5 position (1c, R¹ = Bn, R² = H, X = CH₂) was used, with 2.0 equivalents of enone 2a, the same product (3e) could be obtained with identical ee and slightly decreased yield (70% yield, 80% ee) through an intermolecular Friedel–Crafts, cross-metathesis and intramolecular Friedel–Crafts reaction cascade. In addition, N-1-naphthyl protected pyrrole gave comparable results (3f: 74% yield, 82% ee). The carbon-tethered pyrrole olefin was also compatible under the optimal reaction conditions, affording 3g in 49% yield and 85% ee. Other substituted pyrrole olefins bearing an electron-donating or electron-withdrawing group were also well tolerated and led to their corresponding products (3h–m) in good yields (51–76%) and excellent enantioselectivity (88–93% ee). It is worth noting that aliphatic enone such as methyl vinyl ketone was also a suitable substrate (3n, 88% yield, 88% ee; 3o, 75% yield, 69% ee).

Table 3 Substrate scope of the sequential reaction^a

a Reaction conditions: 1 (0.20 mmol), 2 (0.24 mmol), Zhan-1B (5 mol%), (S)-4c (5 mol%) and 3 Å MS (100 mg) in toluene (2 mL) at 40 °C. b Reaction of 1c (R¹ = Bn, R² = H, X = CH₂) and 2a (R³ = Ph, 0.4 mmol, 2.0 equiv.).

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The advantage of a sequential reaction was demonstrated by comparison with the synthesis of tetrahydroindole 3c in a stepwise approach. The olefin cross-metathesis reaction of pyrrole olefin 1b with phenyl vinyl ketone 2a catalyzed by Zhan-1B gave intermediate 3c′ in 33% yield together with racemic 3c in 52% yield due to its easy cyclization during purification. Tetrahydroindole 3c was then obtained through (S)-4c catalyzed intramolecular Friedel–Crafts alkylation in 33% yield and 83% ee over two steps (Scheme 2). The sequential reaction avoids troublesome separation processes and increases the yield of the synthesis dramatically.

Scheme 2 Stepwise reactions vs. sequential reaction.

In summary, we have developed Zhan-1B in combination with a chiral phosphoric acid catalyzed olefin cross-metathesis/asymmetric intramolecular Friedel–Crafts alkylation of pyrrole derivatives. This sequential catalysis provides a concise and efficient approach to construct chiral 4,5,6,7-tetrahydroindoles in good yields and enantioselectivity from readily available starting materials. Development of more sequential reactions based on dual catalysis is currently ongoing in our laboratory.

Acknowledgements

We thank the National Basic Research Program of China (973 Program 2015CB856600) and the National Natural Science Foundation of China (21272253, 21332009, 21361140373, 21421091) for generous financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1045810. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5qo00034c

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