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Article

Practical Pd(TFA)2-Catalyzed Aerobic [4+1] Annulation for the Synthesis of Pyrroles via “One-Pot” Cascade Reactions

by
Yang Yu
1,†,
Zhiguo Mang
1,†,
Wei Yang
2,
Hao Li
1,* and
Wei Wang
1,3,*
1
State Key Laboratory of Bioengineering Reactor, Shanghai Key Laboratory of New Drug Design, and School of Pharmacy, East China University of Science and Technology, 130 Mei-long Road, Shanghai 200237, China
2
Shanghai Institute of Materia Medica, Shanghai 201203, China
3
Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, NM 87131-0001, USA
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Catalysts 2016, 6(11), 169; https://doi.org/10.3390/catal6110169
Submission received: 21 September 2016 / Revised: 18 October 2016 / Accepted: 21 October 2016 / Published: 31 October 2016
(This article belongs to the Special Issue Organometallic Catalysis for Organic Synthesis)
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Abstract

:
The Pd(TFA)2-catalyzed [4+1] annulation of chained or cyclic α-alkenyl-dicarbonyl compounds and unprotected primary amines for “one-pot” synthesis of pyrroles is reported here. Enamination and amino-alkene were involved in this practical and efficient tandem reaction. The annulation products were isolated in moderate to excellent yields with O2 as the terminal oxidant under mild conditions. In addition, this method was applied to synthesize highly regioselective aminomethylated and di(1H-pyrrol-3-yl)methane products.

Graphical Abstract

1. Introduction

Pyrrole is one of the most significant N-containing heterocycles, and is the component of numerous biologically active molecules [1,2,3], natural products [4,5,6] and functional materials [7,8,9]. For example, atorvastatin A [10,11], which is one of the world’s best-selling drugs, was first introduced to the market in 1997 by Pfizer as an effective HMG-CoA reductase inhibitor for lowering blood cholesterol. Prodigiosin B [12,13], isolated from Serratia marcescens has been continuously investigated for medically relevant properties including antimalarial activity and anticancer activity. Corrole C [14,15] and its derivatives have been used to detect environmental pollutants or biologically important species. In addition, 6,7-dihydro-1H-indol-4(5H)-one and their derivatives also play a more and more important role because of their extensive application as versatile building blocks in organic synthesis. For instance, HSP90 was a therapeutic target for cancer treatment, and compound D [16] possessed a modest level of HSP90 α/β isoform selectivity. R-Ondansetron E [17] is a synthetic drug used to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy, and surgery. Compound F [18] is an antiproliferative compound that has been reported containing antitumor activity (Figure 1).
There has been a long-standing interest in the development of efficient methods for the preparation of highly substituted pyrroles due to their widely biological activities. The classical synthetic methods include Barton–Zard [19], Paal–Knorr [20,21], and Hantzsch reactions [22,23].
However, they suffer from several drawbacks such as harsh reaction conditions, sophisticated operations, and poor availability of the starting materials and functional group tolerance [24]. In recent years, efficient synthetic approaches to construct organic frameworks containing pyrroles have been developed [25,26,27,28,29,30,31,32,33,34,35]. On the other hand, the transition-metal-catalyzed sp2 C–H amination reaction is one of the most demanding procedures to form C–N bonds [36,37]. In recent years, various late transition metal catalysts such as Pd [38,39,40,41], Ru [42], Rh [43], Ir [44], and Cu [45] have been applied in sp2 C–H bond amination. Within this methodology, Pd-catalyzed intramolecular aza-Wacker-type oxidative reactions represent one crucial route to produce a range of 5-membered N-containing heterocycles [46,47,48,49,50,51]. However, intermolecular aza-Wacker-type oxidative amination has been rarely reported and protection of the amine nitrogen is often required in the reaction because palladium species would be deactivated via coordination of the unprotected amine to the metal center in most cases [41,52,53,54]. Furthermore, benzoquinone, Cu(OAc)2 and other inorganic salt have often been used in Wacker oxidative reactions as oxidative reagents [55,56,57]. However, large numbers of organic oxidants or inorganic salts have not been able to meet the requirements of green chemistry and sustainable development. Aiming to deal with these problems, we described the first palladium-catalyzed intermolecular aza-Wacker-type cyclization in 2013, which gave highly substituted pyrroles from 2-alkenyl-1,3-dicarbonyl compounds with unprotected primary amines in a “one-pot” reaction [58]. According to the deuteration studies of the annulation reaction (see supplementary information), a probable mechanism is proposed as shown in Figure 2. Enamine 3 takes place with loss of TFA to generate the Pd-alkyl intermediate II. Then II undergoes β-hydride elimination and Pd–H reinsertion to form IV. The second β-hydride elimination gives pyrrole 4. The Pd(0) is then oxidized by O2 to regenerate catalyst Pd(II).
To continue our research on C–N bond forming reactions [59,60,61,62,63,64,65], we sought to broaden dicarbonyl scope and study the application of the cycloaddition products found as key intermediates in the synthesis of biologically active compounds. Herein, we present a full account of our recent work on the Pd-catalyzed [4+1] annulation reaction.

2. Results and Discussion

2.1. Optimized Synthesis of 4a

In the initial attempt on the formation of pyrroles, when a mixture of 1a and 2a in toluene was heated at 80 °C, enaminone derivative 3a was formed. The reaction mixture was then directly treated with a catalytic amount of Pd(OAc)2 (20 mol %) and was stirred at 60 °C for 16 h. The reaction formed the desired product pyrrole 4a in 48% yield.
Encouraged by the outcome, the solution of 1a (2.0 eq) and 2a (1.0 eq) in toluene was stirred at 60 °C for 16 h in the presence of Pd(OAc)2 (20 mol %). The desired product 4a was obtained in 45% yield (Table 1, entry 1). Next, the reaction conditions were optimized to improve reaction yields (Table 1). The solvent screening revealed that polar aprotic solvents such as dimethylacetamide (DMA), dimethyl sulphoxide (DMSO), and dimethylformamide (DMF) afforded the products in poor yields (entries 2–4). 1,2-Dichloroethane (DCE) gave a slightly higher yield than CH3CN and tetrahydrofuran (THF) (entries 5–7). The results showed that toluene was the most suitable solvent for the reaction. When different oxidants were screened, it was found that air, Cu(OAc)2, and AgOAc were less effective than O2 (entries 8–11). What is more, when Pd(TFA)2 was used as the catalyst, the yield of product 4a was improved to 82% (entry 12). Then other Pd species were screened, and PdCl2, PdCl2(PPh3)2, PdCl(CH3CN)2, and Pd(PPh3)4 were found to afford the products in poor reaction yields (entries 13–16). Additionally, when the reaction was carried out for 1.5 h, a slightly higher yield was achieved (86%, entry 17). Lower catalyst loading needed longer reaction time without any yield sacrifice (entries 18 and 19).

2.2. One-Pot Synthesis of 4

With the optimal reaction conditions in hand, we then examined the substrate scope of the Pd(TFA)2-catalyzed tandem process for the formation of pyrroles 4. As shown in Figure 3, almost all of the tested combinations produced the desired pyrroles 4 in good to excellent isolated yields. Generally, electron-donating groups on the benzene ring have a positive effect on the yield due to enhancement of the nucleophilicity of the nitrogen atom. The substitution pattern of the methoxy group on the phenyl ring of the anilines has a slight impact on the yields (4a–4c) despite a small drop due to the steric effect. The reaction of aniline also proceeds smoothly with 77% yield (4d). Furthermore, the anilines bearing other electron-donating groups on the phenyl ring are also suitable for this protocol (4e–4g). Further, the substrates bearing two substituents on the phenyl ring such as 2-naphthalenamine, 3,4-dimethyaniline, and 4-methoxy-2-methylaniline are also compatible, as illustrated by the formation of the pyrrole products 4h–4j in good yields (74%–85%).
However, the limitation of the process is also recognized; the anilines with electron-withdrawing groups on the phenyl ring give poor yields under this reaction condition (4k and 4l, 40%–50%). Besides, we noted that the aliphatic amines could also engage in the process to afford the corresponding pyrroles 4m and 4n with high yields. Probing the diketone substrates implies that more hindered diketone (R1 = R2 = Et) appears to be a good candidate for this tandem reaction (4o). Moreover, the variation of R2 functionalities on 1 such as Ph and OEt groups lead to the structurally diverse pyrroles 4p–4r in good yields. Finally, we examined the challenging non-terminal alkene substrates. Pyrrole 4s was formed (R3 = Ph) in 65% yield.

2.3. One-Pot Synthesis of 6

To further expand the scope of the reaction, cyclic diketones 5 and primary amine 2 were investigated (Figure 4). When the reaction was carried out under the standard reaction conditions, the yield of desired product was only 38%. However, we were pleased to find that the reaction yield was improved to 71% in 9 h by increasing the catalyst’s loading to 20 mol % (6a). Then, other substrates were examined under the same reaction condition. Both electron-withdrawing and electron-donating substituents on the aniline were tolerated in this reaction. The reaction gave slightly lower yields when R3 was para-MeOPh (6b, 64%). However, when R3 was para-MePh or para-BrPh, the products were formed in moderate yields (6c and 6d). When meta-CF3Ph was tested, the reaction worked with a useful yield (6e). Furthermore, the reaction of aniline, bearing ortho-ClPh, afforded the corresponding product in generally good yield (6f). It is worth mentioning that the reactions proceeded smoothly when the substituted group of the 5-position of cyclic diketone was methyl or dimethyl (6g and 6h). However, the reaction was not tolerable for 5i with phenyl at the 5-position of cyclic diketone (6i).

2.4. Synthesis of Aminomethylated and Di(1H-Pyrrol-3-yl)methane Products

1-Phenyl-6,7-dihydro-1H-indol-4(5H)-one and its derivatives are important intermediates for the synthesis of bioactive compounds. The Cirrincione group reported the synthesis of 7a, which has photochemotherapic activity toward cultured human tumor cells [66]. Martínez and coworkers reported that 7d has cytotoxic activity as DNA intercalator [67] and 7h could work as cyclin-dependent kinases (CDK) inhibitor [68]. These bioactive compounds were synthesized respectively from 6a, 6d, and 6h (Figure 5).
However, the current studies on 6 were focused on modifying the α position of the cyclic ketone. It was found that C-3 of pyrrole was more active than the α position of cycloketone in our study. An aminomethylated product was synthesized smoothly from product 6a through the acetic acid–promoted Mannich reaction of three-component, (CH2O)n, 1-methylpiperazine and 6a. Interestingly, the desired β-aminocarbonyl compound was not formed, and the reaction furnished aminomethylated product 8a at C-3 of pyrrole in 82% yield. In addition, when 6a reacted in the presence of (CH2O)n and HCl instead of 1-methylpiperazine in dioxane, the unexpected di(1H-pyrrol-3-yl)methane derivative 9a was obtained in 78% yield (Figure 6).

3. Experimental Section

3.1. One-Pot Synthesis of 4

All the reactions were carried out under an aerobic atmosphere. To a solution of α-alkenyl-dicarbonyl 1 (1.2 mmol) and amines 2 (0.6 mmol) in dry toluene (2 mL), Pd(TFA)2 (0.03 mmol, 0.05 eq) was added. The reaction mixture with an O2 balloon was stirred for 16 h at 60 °C. The mixture was filtered through celite, washed with methanol (30 mL), the filtrate concentrated, and the residue was purified by column chromatography, hexane/EtOAc (v/v, 20/1 then 10/1) as eluent, giving the desired pyrrole products 4 as an oil.

3.2. Synthesis of 6

All the reactions were carried out under an aerobic atmosphere. To a solution of α- alkenyl diketones 5 (1.2 mmol), and amines 2 (0.6 mmol) in dry toluene (2 mL), Pd(TFA)2 (0.12 mmol, 0.2 eq) was added. The reaction mixture with an O2 balloon was stirred for 9 h at 60 °C. The mixture was filtered through celite, washed with methanol (30 mL), the filtrate concentrated, and the residue was purified by column chromatography, hexane/EtOAc (v/v, 10/1 then 4/1) as eluent, giving the desired pyrrole products 6.

3.3. Synthesis of 8a and 9a

To a suspension of compound 6a (45 mg, 0.2 mmol, 1.0 eq) and polyformaldehyde (18 mg, 0.6 mmol, 3.0 eq) in glacial acetic acid (0.4 mL), N-methyl piperazine (60 mg, 0.6 mmol, 3.0 eq) was added at 25 °C. The mixture was stirred at 25 °C overnight. Water (5 mL) was added, and the pH was then adjusted to pH 8–9 with ammonium hydroxide. The reaction mixture was extracted with dichloromethane. The combined organic phases were washed with water (5 mL × 3), dried over MgSO4, followed by concentration under vacuum, then washed with n-hexane, affording 8a as a pink solid (55 mg, yield 82%).
A solution of 6a (45 mg, 0.2 mmol, 1.0 eq) in dioxane (1.0 mL), polyformaldehyde (18 mg, 0.6 mmol, 3.0 eq) and HCl (conc., 1 mL) was added. The mixture was stirred at 25 °C for 2 h. The solution was concentrated, the crude product was purified by column chromatography on silica gel (PE/EA = 5/1) to give the desired compound 9a as a light yellow powder (36 mg, yield 78%).

4. Conclusions

In summary, we have developed a Pd(TFA)2-catalyzed [4+1] annulation reaction of chained or cyclic α-alkenyl-dicarbonyl compounds with unprotected primary amines. The reaction forms highly substituted pyrroles in a cascade fashion in moderate to excellent yields, and a diverse range of substrates are suitable. The reaction provides a new “one-pot” method for the synthesis of pyrroles. The process uses simple 2-alkenyl-dicarbonyl compounds and primary amines to prepare highly substituted pyrroles in a cascade fashion in moderate to excellent yields for a diverse range of substrates. It is worth noting that unexpected highly regio-selective aminomethylated and di(1H-pyrrol-3-yl)methane products were formed from the annulation products.

Supplementary Materials

The following are available online at www.mdpi.com/2073-4344/6/11/169/s1.

Acknowledgments

This work was supported by the National Science Foundation of China (21372073, 21572054 and 21572055), the Fundamental Research Funds for the Central Universities and the China 111 Project (Grant B07023).

Author Contributions

Yang Yu and Zhiguo Mang performed the experiments of the cyclic α-alkenyl-dicarbonyl compounds and analyzed the data. Wei Yang contributed to the other experiments. Yang Yu wrote the first draft of the manuscript that was then improved by Hao Li and Wei Wang.

Conflicts of Interest

The authors declare no conflict of interest.

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Catalysts 06 00169 g001 550
Figure 1. Bioactive compounds containing pyrroles.
Figure 1. Bioactive compounds containing pyrroles.
Catalysts 06 00169 g001
Catalysts 06 00169 g002 550
Figure 2. Proposed mechanism of Pd(TFA)2-catalyzed [4+1] annulation.
Figure 2. Proposed mechanism of Pd(TFA)2-catalyzed [4+1] annulation.
Catalysts 06 00169 g002
Catalysts 06 00169 g003 550
Figure 3. Scope of Pd(TFA)2-catalzyed synthesis of pyrroles 4. a Isolated yield. b 20 mol % catalyst was used.
Figure 3. Scope of Pd(TFA)2-catalzyed synthesis of pyrroles 4. a Isolated yield. b 20 mol % catalyst was used.
Catalysts 06 00169 g003
Catalysts 06 00169 g004a 550Catalysts 06 00169 g004b 550
Figure 4. Scope of Pd(TFA)2-catalzyed synthesis of pyrroles 6. a Isolated yield.
Figure 4. Scope of Pd(TFA)2-catalzyed synthesis of pyrroles 6. a Isolated yield.
Catalysts 06 00169 g004aCatalysts 06 00169 g004b
Catalysts 06 00169 g005 550
Figure 5. Synthetic transformation of 6 according to the literature.
Figure 5. Synthetic transformation of 6 according to the literature.
Catalysts 06 00169 g005
Catalysts 06 00169 g006 550
Figure 6. Further transformation of 6a.
Figure 6. Further transformation of 6a.
Catalysts 06 00169 g006
Table
Table 1. Optimized Synthesis of 4a a.
Table 1. Optimized Synthesis of 4a a.
Catalysts 06 00169 i001
EntrySolventCatalystOxidantYield b (%)
1toluenePd(OAc)2air45
2DMAPd(OAc)2air18
3DMSOPd(OAc)2air12
4DMFPd(OAc)2air32
5DCEPd(OAc)2air40
6CH3CNPd(OAc)2air23
7THFPd(OAc)2air25
8xylenesPd(OAc)2air50
9xylenesPd(OAc)2Cu(OAc)221
10xylenesPd(OAc)2AgOActrace
11xylenesPd(OAc)2O258
12xylenesPd(TFA)2O282
13xylenesPdCl2O228
14xylenesPdCl2(PPh3)2O214
15xylenesPdCl2(CH3CN)2O2trace
16 cxylenesPd(PPh3)4O217
17 dtoluenePd(TFA)2O286
18 etoluenePd(TFA)2O285
19 ftoluenePd(TFA)2O288
a A solution of 1a (1.2 mmol) and 2a (0.6 mmol) with catalyst (0.03 mmol) in the solvent (2 mL) was stirred at 60 °C for 16 h. b Isolated yield. c The reaction time is 2 h. d The reaction time is 1.5 h. e 10 mol % catalyst was used with the reaction time of 9 h. f 5 mol % catalyst was used with the reaction time of 16 h.

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MDPI and ACS Style

Yu, Y.; Mang, Z.; Yang, W.; Li, H.; Wang, W. Practical Pd(TFA)2-Catalyzed Aerobic [4+1] Annulation for the Synthesis of Pyrroles via “One-Pot” Cascade Reactions. Catalysts 2016, 6, 169. https://doi.org/10.3390/catal6110169

AMA Style

Yu Y, Mang Z, Yang W, Li H, Wang W. Practical Pd(TFA)2-Catalyzed Aerobic [4+1] Annulation for the Synthesis of Pyrroles via “One-Pot” Cascade Reactions. Catalysts. 2016; 6(11):169. https://doi.org/10.3390/catal6110169

Chicago/Turabian Style

Yu, Yang, Zhiguo Mang, Wei Yang, Hao Li, and Wei Wang. 2016. "Practical Pd(TFA)2-Catalyzed Aerobic [4+1] Annulation for the Synthesis of Pyrroles via “One-Pot” Cascade Reactions" Catalysts 6, no. 11: 169. https://doi.org/10.3390/catal6110169

APA Style

Yu, Y., Mang, Z., Yang, W., Li, H., & Wang, W. (2016). Practical Pd(TFA)2-Catalyzed Aerobic [4+1] Annulation for the Synthesis of Pyrroles via “One-Pot” Cascade Reactions. Catalysts, 6(11), 169. https://doi.org/10.3390/catal6110169

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