Asymmetric dearomatization of pyrrolesviaIr-catalyzed allylic substitution reaction: enantioselective synthesis of spiro-2H-pyrroles

Abstract

Asymmetric dearomatization of pyrroles has been accomplished by using Ir-catalyzed intramolecular asymmetric allylic alkylation reactions. Reactions of allylic carbonate tethered pyrroles in the presence of [Ir(cod)Cl]₂ and a BINOL-derived phosphoramidite ligand lead to efficient generation of spiro-2H-pyrrole derivatives with up to 96% ee.

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The pyrrole moiety serves as the key structural core of numerous biologically active natural products and pharmaceutical agents.^1,2 However, enantioselective transformations of pyrroles have not been fully explored.³Pyrroles have similar structural and electronic properties as do indoles, which readily participate in selective Friedel–Crafts alkylation reactions as a consequence of the fact that the 3-position of indoles is much more reactive with electrophiles.⁴ In contrast, relatively few Friedel–Crafts alkylation reactions of pyrroles are known, perhaps a result of a regioselectivity issue caused by the fact that the 2- and 3-positions of pyrroles display similar reactivity with electrophiles.⁵ In addition, alkylated pyrroles are generally more reactive than their parent pyrroles, a property that makes highly selective formation of mono-alkylated products a challenging issue.⁶

Enantioselective preparation of substituted spiro-2H-pyrrole derived substructures, which are interesting synthetic intermediates and scaffolds for drug discovery, remains a significant goal in synthetic organic chemistry (Fig. 1).⁷ Important problems confront the synthesis of substituted spiro-2H-pyrroles, including regioselectivity and dearomatization, both of which are known to be unfavourable processes. Although seemingly straightforward, to our knowledge no catalytic enantioselective synthetic methods exist for generating these important synthetic intermediates from pyrroles(eqn (a)).

Fig. 1 Selected naturally occurring compounds bearing spiro-2H-pyrrole and spiro-pyrrolidine units.

As part of a continuing research program focusing on asymmetric dearomatization reactions,^8,9 we have explored catalytic asymmetric dearomatization reactions of pyrroles. Recently, Reddy and Davies have elegantly demonstrated that N-protected pyrroles undergo [4 + 3] cycloaddition reactions with vinyldiazoacetates in the presence of a chiral Rh-complex to produce tropanes in good yields and with excellent ee.¹⁰ In an exploration aimed at uncovering methods to carry out efficient synthesis of enantioenriched spiro-2H-pyrroles bearing a chiral quaternary carbon center, we recently probed intramolecular allylic dearomatization reactions of pyrroles. In spite of the reactivity issues mentioned above, these reactions proceed in high yields with excellent levels of chemo-, regio-, and enantioselectivities. Below, we describe the results of this effort which has resulted in the development of a method for the enantioselective synthesis of spiro-2H-pyrroles that utilizes an Ir-catalyzed asymmetric allylic dearomatization reaction of pyrroles.

Studies of this problem were initiated by an exploration of the reaction of the allylic carbonate tethered pyrrole 2a with an Ir-catalytic system comprised of [Ir(cod)Cl]₂ and the phosphoramidite ligand 1a (Table 1).¹¹ In the presence of 2 mol% of [Ir(cod)Cl]₂, 4 mol% of 1a, and 1.0 equiv. of Cs₂CO₃, reaction of 2a in THF for 15 h gave the spiro-2H-pyrrole 3a in 69% yield, 99/1 dr and 87% ee (entry 1, Table 1). In order to optimize the reaction conditions, various bases such as K₃PO₄, DBU, DABCO and Li₂CO₃ were screened (entries 2–5, Table 1). This exploration led to the finding that Cs₂CO₃ is the optimal base for the process. The effects of different chiral ligands were examined next. Ligands 1b and 1c were observed to form catalysts that catalyze the reaction of 2a with good ee, but with only moderate yields and dr. In addition, Ir catalysts containing ligands 1d and 1e were not effective in promoting the allylic dearomatization process. Interestingly, screening of ligands 1f, 1g, and 1h that were developed in our earlier work¹² demonstrated that the catalyst derived from 1f gave satisfactory results in terms of yield, dr and ee (entry 10, Table 1). Also, screening of various solvents (entries 13–16, Table 1) led to the identification of THF as being ideal. Finally, the effects of substrate concentration, base loading and temperature were probed (entries 17–19, Table 1). In combination with observations made in other optimization studies, the results showed that the best conditions for the reaction of 2a are THF (0.1 M) with 2 mol% of [Ir(cod)Cl]₂, 4 mol% 1f, and 1.0 equiv. of Cs₂CO₃ at 50 °C. This process produces spiro-2H-pyrrole 3a in 80% yield, 99/1 dr and 93% ee (entry 10, Table 1).

Table 1 Optimization of the reaction conditions.^a

Entry	Ligand	Solvent	Base	t/h	Yield (%)^b	dr^c	ee (%)^d
a Reaction conditions: 0.1 mmol of 2a, 0.1 mmol of base in solvent (1.0 mL) at 50 °C or under reflux. b Isolated yield of the major diastereoisomer. c Determined by ^1H NMR of the crude reaction mixture. d Determined by HPLC analysis. e Reaction was performed in 2.0 mL solvent. f Reaction was performed with 2.0 equiv. of base. g Reaction was performed at room temperature.
1	1a	THF	Cs2CO3	15	69	99/1	87
2	1a	THF	K3PO4	34	60	99/1	86
3	1a	THF	DBU	34	46	99/1	88
4	1a	THF	DABCO	34	16	85/15	86
5	1a	THF	Li2CO3	34	62	99/1	85
6	1b	THF	Cs2CO3	38	64	89/11	83
7	1c	THF	Cs2CO3	38	53	88/12	84
8	1d	THF	Cs2CO3	38	Trace	—	—
9	1e	THF	Cs2CO3	38	Trace	—	—
10	1f	THF	Cs2CO3	21	80	99/1	93
11	1g	THF	Cs2CO3	21	69	91/9	84
12	1h	THF	Cs2CO3	39	Trace	—	—
13	1f	DCM	Cs2CO3	21	82	83/17	88
14	1f	Toluene	Cs2CO3	21	72	93/7	92
15	1f	Dioxane	Cs2CO3	21	74	95/5	89
16	1f	Et2O	Cs2CO3	21	80	91/9	93
17^e	1f	THF	Cs2CO3	21	71	94/6	88
18^f	1f	THF	Cs2CO3	21	69	99/1	90
19^g	1f	THF	Cs2CO3	39	67	96/4	88

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Employing the optimized conditions, reactions of various 2-pyrrolyl allylic carbonates were explored to examine the generality of the process (Table 2). The stereochemistry of the products of these processes was assigned based on the results of X-ray crystallographic analysis of enantiopure 3g.‡ Reactions of allylic carbonates containing various protecting groups (Bn, allyl, 4-Br-C₆H₄CH₂) on the amine moiety in the tether all gave the corresponding spiro-2H-pyrrole products in good yields with excellent dr and ee (79–85% yield, 95/5–99/1 dr, 86–93% ee, entries 1–3, Table 2). Notably, substrate 2d, containing an N-methyl tertiary amine group, did not react smoothly (47% yield, 91/9 dr, 81% ee) under the optimized conditions. However, by switching the ligand in the catalyst to 1a, this reaction generated 3d in good yield with excellent dr and ee (77% yield, >99/1 dr, 94% ee, entry 4, Table 2). Substrates bearing either electron-donating (4-Me, 4-MeO, 3,4-(MeO)₂) (entries 5–8, Table 2) or electron-withdrawing groups (4-Cl, 4-F) (entries 9–10, Table 2) on the 5-phenyl moiety (R²) on the pyrrole core all reacted to form the corresponding products in good yields, dr and ee (82–90% yield, 92/8–97/3 dr, 84–95% ee). Importantly, reaction took place smoothly on the substrate 2k, in which an alkyl group is present at the pyrrole 5-position (forming 3k, 83% yield, 96% ee, 90/10 dr, entry 11, Table 2). However, the pyrrole 2l, bearing no substituent at C-5, reacted inefficiently under the optimized conditions outlined above to give a low yield and ee of 3l (21% yield, 57% ee). In contrast, by using the catalyst containing ligand 1a, the yield of this process was improved and excellent dr and ee were obtained (61% yield, 97/3 dr, 96% ee, entry 12, Table 2). Unfortunately, when the carbon tethered substrate was used, only a trace amount of the corresponding product could be observed.

Table 2 The reaction substrate scope

Entry	2, R^1, R^2	3	Yield (%)^a	dr^b	ee (%)^c
a Isolated yields of the major diastereoisomer. b Determined by ^1H NMR of the crude reaction mixture. c Determined by HPLC analysis. d Reaction was performed with 1a as ligand.
1	2a, Bn, Ph	3a	80	99/1	93
2	2b, allyl, Ph	3b	85	95/5	86
3	2c, 4-Br-C6H4CH2, Ph	3c	79	96/4	90
4^d	2d, Me, Ph	3d	77	>99/1	94
5	2e, Bn, 4-Me-C6H4	3e	83	93/7	84
6	2f, Bn, 4-MeO-C6H4	3f	88	97/3	95
7	2g, 4-Br-C6H4CH2, 4-MeO-C6H4	3g	82	97/3	95
8	2h, Bn, 3,4-(MeO)2-C6H3	3h	82	94/6	91
9	2i, Bn, 4-Cl-C6H4	3i	88	92/8	86
10	2j, Bn, 4-F-C6H4	3j	90	92/8	89
11	2k, Bn, Et	3k	83	90/10	96
12^d	2l, Bn, H	3l	61	97/3	96

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To demonstrate the utility of the newly developed methodology, several transformations of the spiro-2H-pyrrole products were carried out. As shown in Scheme 1, treatment of 3l with sodium borohydride afforded the spiro-2,5-dihydropyrrole 4 in 90% yield (Scheme 1, eqn (1)). The spirolactam 5 was obtained via a two-step route, involving sequential treatment with NaClO₂ and sodium borohydride (Scheme 1, eqn (2)).^13,14 When compound 3l was subjected to Pd/C-catalyzed hydrogenation conditions using 600 psi of hydrogen, spiropyrroline 7 was formed in 75% yield. Interestingly, when this process was carried out under 1 atm of hydrogen, spiro-3,4-dihydropyrrole 6 was produced in 65% yield (Scheme 1, eqn (3) and (4)). The results suggest that selective hydrogenation of the C=C over the C=N bond is possible, a phenomenon that should enhance the synthetic utility of the spiro-2H-pyrrole products. Notably, the C=N bond of product 3g, bearing an aryl substituted imine, could not be reduced using sodium borohydride but it was transformed to amine 8 when sodium cyanoborohydride in acetic acid was employed (Scheme 1, eqn (5)).^13,15 In all processes, no notable loss of enantiomeric purity took place.

Scheme 1 Transformation of the products.

In summary, the investigation described above has led to the development of the first Ir-catalyzed intramolecular asymmetric allylic dearomatization reaction of pyrroles. The spiro-2H-pyrrole derivatives were generated in these reactions in good yields with up to >99/1 dr and 96% ee. Extensions of the scope and applications of the spiro-2H-pyrrole forming processes are currently under study in our laboratory.

Acknowledgements

We thank the National Basic Research Program of China (973 Program 2009CB825300), the NSFC (20821002, 20923005, 21025209), and the Chinese Academy of Sciences for generous financial support of this research.

Notes and references

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Footnotes

† Dedicated to Professor Christian Bruneau on the occasion of his 60th birthday.

‡ Electronic supplementary information (ESI) available: Experimental procedures and analysis data for new compounds, CIF file of 3g. CCDC reference number 824629. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c1sc00517k

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