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Highly Atroposelective Synthesis of Arylpyrroles by Catalytic Asymmetric Paal-Knorr Reaction Lei Zhang, Jian Zhang, Ji Ma, Dao-Juan Cheng, and Bin Tan J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 20 Jan 2017 Downloaded from http://pubs.acs.org on January 20, 2017
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Journal of the American Chemical Society
Highly Atroposelective Synthesis of Arylpyrroles by Catalytic Asymmetric Paal-Knorr Reaction Lei Zhang,†‡ Jian Zhang,† Ji Ma,† Dao-Juan Cheng,† and Bin Tan*† †
Department of Chemistry, South University of Science and Technology of China, Shenzhen, 518055, China Key Laboratory of Biomedical Polymers of Ministry of Education, College of Chemistry and Molecular Science, Wuhan University, Wuhan, 430072, China
‡
Supporting Information Placeholder ABSTRACT: A general and efficient method for accessing enantiomerically pure arylpyrroles by utilizing the catalytic asymmetric Paal-Knorr reaction has been developed for the first time. A wide range of axially chiral arylpyrroles were obtained in high yields with good to excellent enantioselectivities. The key to success is the use of the combined-acid catalytic system involving a Lewis acid and a chiral phosphoric acid for achieving effective enantiocontrol. Noteworthy is that an unexpected solventdependent inversion of the enantioselectivity was observed in the above-mentioned asymmetric reaction.
As one of the most prominent classes of heterocyclic compounds, pyrroles are key structural motifs in biologically active compounds and useful building blocks in the synthesis of natural products, as well as in material sciences.1,2 Accordingly, their synthesis has always been among the most important research areas in synthetic chemistry and numerous methods have been widely developed.2 One of the most common approaches for the construction of pyrroles is the Paal-Knorr reaction in which 1,4diketones are converted into pyrroles from the reaction with primary amine or ammonia by acid-mediated dehydrative cyclization.3 Remarkably, this reaction was first reported in 1884 (Scheme 1a), however, catalytic asymmetric Paal-Knorr pyrrole synthesis still remained elusive to date. One of the easily missing reasons is the absence of intrinsic chirality at the pyrrole, revealing no obvious handle for asymmetric induction. We questioned whether the formation of chiral pyrroles in the course of the reaction would be feasible. Here we report an acid-catalyzed asymmetric Paal-Knorr reaction for atroposelective synthesis of axially chiral arylpyrroles (Scheme 1b). Scheme 1. Paal-Knorr Reaction for Pyrrole Synthesis
Axially chiral biaryl compounds are prevalent in biologically active compounds, natural products as well as materials, and also play a significant role in acting as chiral ligands or organocatalysts.4 Owing to the importance of this structural motif, the catalytic atroposelective construction of biaryl scaffolds has been intensively investigated and great progress has been accomplished in recent years.4,5 In sharp contrast, the asymmetric synthesis of axially chiral arylpyrroles remains largely unexplored, although it exists in natural products (Marinopyrrole, Murrastifoline-F),6 antiHIV inhibitor (PBO)7 and recently as chiral ligands8 for asymmetric addition reactions (Scheme 2). However, the effective synthesis of optically pure arylpyrroles relies on conventional resolution,9 which requires the stoichiometric amounts of chiral reagents. Therefore, the development of a catalytic asymmetric synthesis of axially chiral arylpyrroles is very challenging and highly appealing. Scheme 2. The Biologically Active Compounds and Ligand with Arylpyrrole Skeleton Cl O N OH O Cl
Cl O
N OH
NH Cl Marinopyrrole
OMe
N
N O
N H
OMe Murrastifoline-F
N
Me
OH
F3C Ph
anti-HIV inhibitor PBO
Ph
amino alcohol Chiral ligand
To address this issue, we envisioned that chiral phosphoric acids (CPA),10 which have emerged as powerful organocatalysts for various reactions within the past twelve years, may be capable of facilitating this transformation enantioselectively by accelerating the intramolecular nucleophilic addition to form hemiaminal on the basis of previous mechanistic investigation on Paal-Knorr reaction. Motivated by the previous elegant work involving asymmetric Fischer indolization,11 and as part of our ongoing interest in asymmetric construction of axially chiral compounds12 and phosphoric acid catalysis,13 we describe herein the results of the investigation, leading to the first phosphoric acid-catalyzed atroposelective synthesis of axially chiral arylpyrroles via asymmetric Paal-Knorr pyrrole synthesis. To validate the feasibility of the hypothesis, we initially conducted the Paal-Knorr reaction of 1,4-dione 1a with 2-(tertbutyl)aniline 2a in CCl4 at room temperature in the presence of 10 mol% of spinol-derived phosphoric acid14 (R)-C1 (Table 1, entry 1). Encouragingly, despite its high steric hindrance, the reaction
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proceeded smoothly to give the axially chiral arylpyrrole 3aa in 94% yield with 68% ee. This proof-of principle result obviously indicates that the control of axial chirality of arylpyrroles by using the chiral phosphoric acid-catalyzed asymmetric Paal-Knorr pyrrole synthesis was feasible. Having thus proven the efficiency of the chiral phosphoric acid in the current system, we next turned our attention to investigate the substituent effects and the axially chiral backbone on the catalysts (Table 1, entries 2-10). As shown in Table 1, the electron property and steric bulk on the aromatic ring, as well as backbone have very strong influences on enantioselectivity. We were glad to find catalyst (S)-C3 gave the best result in terms of the enantioselectivity (72% ee) (Table 1, entry 3). The remarkable solvent effects were observed in this transformation (Table 1, entries 11-14 and Table S1 in Supporting Information (SI)). It is noteworthy that the absolute configuration of the obtained product was reversed by only changing the solvent from CCl4 to methanol (entry 14). The enantioselectivity was also affected by the reaction temperature and reagents (Table 1, entries 15-16 and Table S1 in SI). Inspired by Yamamoto’s combinedacid catalysis principle15 and Luo’s binary-acid catalysis,16 in which the phosphoric acid could be activated by a Lewis acid to promote many challenging transformations, we imagined that the combined-acid system may prove a good opportunity to improve the enantioselectivity of the model reaction via synergistic interaction between the substrates and the catalysts. Therefore, we further optimized the reaction conditions by adding Lewis acids to the reaction system. To our delight, 10 mol% of Fe(OTf)3 promoted the reactions very well and the enantioselectivity was improved to 88% ee (Table 1, entries 17-18 and Table S2 in SI). Finally, we identified the following protocol as optimal: When 1a was treated with 2a in the presence of catalyst (S)-C3 (10 mol%) and Fe(OTf)3 (10 mol%) in the mixture of CCl4 (0.3 mL) and cyclohexane (1.2 mL) at 0 oC for 4 days, the axially chiral 3aa was obtained in 95% isolated yield with 96% ee (Table 1, entry 18).
16d 17e 18e
(S)-C3 (S)-C3 (S)-C3
0 0 0
CCl4 CCl4 -f
84 85 95
78 88 96
a
Unless otherwise stated, all reactions were carried out with 1a (0.15 mmol), 2a (0.1 mmol), CPA (0.01 mmol) in CCl4 (1 mL) at rt or 0 °C. b Isolated yield. c Determined by chiral HPLC analysis. d MgSO4 (100 mg) was added. e MgSO4 (100 mg) and Fe(OTf)3 (10 mol%) were added. f CCl4/cyclohexane (0.3 mL/1.2 mL) as solvents.
With the optimized conditions in hand, we next examined the substrate scope of various substituted 1,4-diketones. As shown in Table 2, different substituents and substitution patterns on the aromatic ring of the substrates (1a-1m) were all tolerated to give the corresponding products 3aa-3am in 85-95% yields with 8697% ee. Moreover, the substituted phenyl group could be replaced with naphthyl (1n) or heteroaryl (1o) group without obviously affecting the reaction results (3an and 3ao). Encouraged by these results, we expanded the generality of the reaction with regard to variation of ester functional groups. The desired products (Table 2, 3ap-3as) were formed with good axial chirality control and the transformation proceeded almost equally well with different groups, demonstrating the broad generality of this approach for the synthesis of axially chiral arylpyrrole derivatives. Table 2. The Substrate Scope with Respect to 1,4-Diketonesa R (S)-C3 (10 mol%)
NH2
R
O
t-Bu
+
Ar
Fe(OTf)3 (10 mol%)
1a-1s CO2Me N R 3aa-3aj
3aa-3as 3af, R = 4-Cl,
3ab, R = 4-Br, 5.0 d, 90%, 92%ee 3ad, R = 4-F, 5.0 d, 86%, 90%ee
3ag, R = 3-CF3, 4.0 d, 94%, 96%ee 3ah, R = 4-CF3, 4.0 d, 85%, 94%ee 3ai, R = 3-H, 4.0 d, 93%, 90%ee
3ae, R = 3-Cl, 4.0 d, 93%, 95%ee
3aj R = 4-Me, 4.0 d, 91%, 86%ee
CO2Me F
N
t-Bu
Cl
3ak, 4.0 d, 94%, 94% ee
3ao, 4.5 d, 93%, 86% ee
t-Bu
3an, 4.5 d, 86%, 86% ee
CO2iPr
N t-Bu
N t-Bu
3am, 3.5 d, 93%, 97% ee
CO2Et
N S
CO2Me
N
F
3al, 4.0 d, 92%, 95% ee
CO2Me
4.0 d, 94%, 92%ee
CO2Me F3C
N t-Bu
t-Bu
2a
CO2Me
Cl
N
3aa, R = 3-Br, 4.0 d, 95%, 96%ee 3ac, R = 3-F, 3.5 d, 91%, 95%ee
t-Bu
Ar
CCl4/cyclohexane MgSO4, 0 C
O
Cl
Table 1. Optimization of the Reaction Conditionsa
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CO2allyl
N t-Bu
CO2Bn N
N t-Bu
t-Bu
t-Bu
Br
Br
Br
Br
3ap, 4.0 d, 94%, 96% ee
3aq, 4.0 d, 92%, 96% ee
3ar, 4.0 d, 90%, 95% ee
3as, 4.0 d, 91%, 94% ee
a
entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
catalyst T (ºC) solvent yield (%)b (R)-C1 rt CCl4 94 (R)-C2 rt CCl4 90 rt CCl4 94 (S)-C3 (S)-C4 rt CCl4 91 (S)-C5 rt CCl4 93 (S)-C6 rt CCl4 92 (S)-C7 rt CCl4 90 (R)-C8 rt CCl4 92 (R)-C9 rt CCl4 91 (S)-C10 rt CCl4 92 rt DCM 71 (S)-C3 (S)-C3 rt toluene 89 (S)-C3 rt cyclohexane 92 (S)-C3 rt MeOH 57 0 CCl4 82 (S)-C3
ee (%)c -68 -13 72 70 66 53 14
