Cu-Catalyzed Tandem Aerobic Oxidative Cyclization for the Synthesis

Letter Cite This: Org. Lett. 2018, 20, 5048−5052

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Cu-Catalyzed Tandem Aerobic Oxidative Cyclization for the Synthesis of 3,3′-Bipyrroles from the Homopropargylic Amines Zhenjie Qi,† Yong Jiang,‡ Bingxiang Yuan,† Yanning Niu,§ and Rulong Yan*,† †

Org. Lett. 2018.20:5048-5052. Downloaded from pubs.acs.org by UNIV OF THE WESTERN CAPE on 08/17/18. For personal use only.

State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Gansu, China ‡ School of Chemistry and Chemical Engineering, Yangtze Normal University, Chongqing, China § Department of Teaching and Research, Nanjing Forestry University, Huaian, China S Supporting Information *

ABSTRACT: A Cu-catalyzed method for the synthesis of 3,3′bipyrroles from homopropargylic amines through tandem aerobic oxidative cyclization involving the formation of C−C bond has been developed. The features of this reaction are a small number of Cu catalysis and simple starting substrates. Moreover, this procedure exhibits good functional group tolerance and a series of 3,3′-bipyrroles derivatives are obtained in moderate to good yields.

S

Scheme 1. Synthesis of Substituted 3,3′-Bipyrroles

ubstituted pyrroles, as privileged heterocyclic compounds, are found in many natural products,1 pharmaceutical agents,2 and materials science.3 Furthermore, pyrrole moieties have also emerged as important functional groups in biologically active compounds.4 Accordingly, the construction of the pyrrole scaffolds has attracted intensive research interest and many synthetic methods have been developed.5 Nevertheless, most known methods are effective for the synthesis of a single pyrrole ring.6 Efficient synthetic strategies for the generation of substituted 3,3′-bipyrroles are very rare. Bipyrrole and their derivatives are widespread in natural products,7 materials science,8 and medicinal chemistry.9 Until now, the approach for the synthesis the substituted 3,3′bipyrroles has been very limited. Traditional methods for the synthesis of substituted 3,3′-bipyrroles focus on the functionalization of the preconstructed pyrrole nucleus, as reported by the Uno group (Scheme 1).7c,10 The group of Hua also has developed a straightforward method for the synthesis of 3,3′bipyrroles by oxidative C−H homocoupling of 1,2,5trisubstituted pyrroles in the presence of FeCl3.10e Hence, research on the synthesis of 3,3′-bipyrroles based on construction of pyrrole scaffolds is even less. Gleiter’s group has reported that Pd-catalyzed rearrangement of 1,6diisopropyl-1,6-diazacyclodeca-3,8-diyne to N,N′-diisopropyl3,3′-bispyrrole in a one-pot reaction involving the formation of a C−C bond.11 The group of Jaisankar disclosed that 3,3′-bipyrroles could be synthesized from diaroylacetylene, the appropriate 1,3dicarbonyls, and ammonium acetate through double Michael addition reaction.12 Although these impressive advances have been achieved based on construction of pyrrole scaffolds, the synthesis of 3,3′-bipyrroles from simple substrates still remains a great challenge. Herein, our group reports a Cu-catalyzed © 2018 American Chemical Society

method for the synthesis of 3,3′-bipyrroles from the simple homopropargylic amines via C−C and C−N bond formations. Initially, investigation commenced with the reaction of N-(3phenylprop-2-yn-1-yl)aniline (1a) and CuCl (10 mol %) in toluene at 110 °C under a nitrogen atmosphere. The 1,1′,2,2′Received: July 14, 2018 Published: August 1, 2018 5048

DOI: 10.1021/acs.orglett.8b02201 Org. Lett. 2018, 20, 5048−5052

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Organic Letters Scheme 3. Scope of Aminoalkynesa

tetraphenyl-1H,1′H-3,3′-bipyrrole (2a) was formed in 31% yield (Table S1, entry 1). The structure of 2a was determined by X-ray crystallographic analysis. After extensive screening of different reaction parameters (see Supporting Information (SI), Table S1), the optimum conditions were identified to be CuCl (5 mol %) in DMSO at 110 °C under an air atmosphere (entry 13). With the optimized reaction conditions established, the universality and scope were subsequently investigated, and the results are illustrated in Scheme 2. To our delight, Scheme 2. Scope of Aminoalkynesa

a

Reaction conditions: 1a (0.3 mmol), CuCl (5 mol %), DMSO (2 mL), 110 °C, air.

yields of R1 substituents with electron-donating groups were slightly higher than with the electron-withdrawing groups. As good results were obtained with the R1 substituents as an aryl group, we turned our attention to R1 substituents as an alkyl group. As shown in Scheme 3, the substrates with alkyl groups performed well in this process and the desired products were afforded in good yields (4l−4p). However, the substrate 3q cannot work and no desired product 4q was detected. Moreover, the homopropargylic amines with two different functional groups on the phenyl ring of R1 and R2 were also suitable for this transformation, generating the desired products in good yields (4r, 4s). More challenging substrates were also evaluated in this reaction, and the results are illustrated in Scheme 4. When N-

a Reaction conditions: 1a (0.3 mmol), CuCl (5 mol %), DMSO (2 mL), 110 °C, air.

homopropargylic amines with different groups on benzene rings of R2 substituents performed well and the desired products were isolated in ideal yields (2b−2k). In general, homopropargylic amines with an electron-donating group on benzene rings showed higher reactivity than those with an electron-withdrawing group (2b−2i). These results may be caused by the increased reactivity of the alkynyl group in homopropargylic amines with electron-donating groups. Naphthalen-1-yl homopropargylic amine was also a suitable substrate for this process, giving the desire product 2l in 52% yield. Moreover, the standard conditions were also tolerated with heteroarene homopropargylic amines such as quinolyl and thienyl and the corresponding products were obtained in 45% and 51% yields, respectively. The substrates 1o and 1p with H and alkyl groups cannot work in this method, and no desired products were detected. Furthermore, the scope of the substrate investigation was enlarged to substituents R1 of homopropargylic amines, and the results are shown in Scheme 3. Under the optimized reaction conditions, the substrates with different groups on the benzene ring of R1 substituents were compatible with this transformation and generated the desired products in moderate yields (4b−4k). Similar to R2 substituents, the

Scheme 4. Scope of 3,3′-Bipyrroles

(1,4-diphenylbut-3-yn-1-yl)aniline 5a and N-(1-(4-chlorophenyl)-4-phenylbut-3-yn-1-yl)aniline 5b were subjected to the standard conditions, the expected products 6a and 6b were isolated in 51% and 60% yields, respectively. In order to obtain further insight into this reaction, several control experiments were carried out in Scheme 5. First, the radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy 5049

DOI: 10.1021/acs.orglett.8b02201 Org. Lett. 2018, 20, 5048−5052

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Organic Letters Scheme 5. Control Experiments

Scheme 6. Proposed Mechanism

intermediate 14. Finally, the desired product 2a is afforded through oxidation catalyzed by CuCl. In conclusion, we have developed a direct protocol to synthesize 3,3′-bipyrroles from aminoalkynes with CuCl catalysis. Broad group tolerance makes this method useful to construct such unique scaffolds from simple aminoalkynes, and the desired 3,3′-bipyrroles are afforded in ideal yields.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02201. Experimental methods, X-ray data for 2a, and 1H and 13 C NMR spectra of all compounds (PDF)

(TEMPO) and 2,6-di-tert-butyl-4-methyl-phenol (BHT) were employed for this reaction. The reactions were significantly inhibited when 2.0 equiv of BHT or TEMPO were used. The results demonstrate that this transformation should be a radical pathway under the standard conditions. Then the substrate 1phenyl-1H-pyrrole was used to trap the radical intermediate. Unfortunately, no useful radical intermediate was detected. Further study disclosed that the compound 7 was isolated in 22% yield under standard reaction conditions after 15 min and disappeared as the experiment proceeded. Then compound 7 was used as the substrate under the optimized conditions, and the desired product 2a was afforded in 71% yield. Consistent with our expectation, the intermediate 7 was subject to the optimized conditions with TEMPO (2.0 equiv) and no desired product was formed. Based on the above results, compound 7 should be the intermediate for this reaction. Moreover, the HRMS (High Resolution Mass Spectrometry) measurement was also performed with compound 7 proceeding under standard conditions after 15 min. To our delight, the important peaks at m/z = 222.1275, 457.2266, and 439.2162 corresponding to C16H16N [M + H]+, C32H29N2O [M + H]+, C32H27N2 [M + H]+ were observed (Figure S1, SI). These results indicate that the intermediates 10, 13, and 14 possibly exist in this transformation. On the basis of the above results, a plausible mechanism is proposed as shown in Scheme 6. The intermediate 7 is generated from the substrate 1a through first the coordination of CuCl and then nucleophilic attraction of H2O under the standard conditions. Then radical intermediate 8 is formed through oxidation. Meanwhile, the intermediate 9, which is obtained from 7 through intramolecular cyclization, gives the cyclic compound 10 with hydrogen ion elimination. Radical addition between intermediate 8 and 10 produces the radical intermediate 11. Then 12 is generated from 11, giving compound 13 via oxidative aromatization with Cu-catalysis. Intermolecular cyclization occurs with 13 to form the

Accession Codes

CCDC 1843793 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Zhenjie Qi: 0000-0002-0784-3188 Yong Jiang: 0000-0002-7300-9984 Rulong Yan: 0000-0002-0450-3065 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (21672086), the Gansu Province Science Foundation for Youths (1606RJYA260), and the Fundamental Research Funds for the Central Universities (lzujbky-2018-81).

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REFERENCES

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DOI: 10.1021/acs.orglett.8b02201 Org. Lett. 2018, 20, 5048−5052