A One-Pot Construction of Halogenated Trifluoromethylated Pyrroles

Letter pubs.acs.org/OrgLett

A One-Pot Construction of Halogenated Trifluoromethylated Pyrroles through NXS (X = Br, I) Triggered Cascade Chaoqian Huang,† Yu Zeng,† Huayu Cheng,† Anjing Hu,† Lu Liu,† Yuanjing Xiao,*,† and Junliang Zhang*,†,‡ †

Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, 3663 N. Zhongshan Road, Shanghai 200062, PR China ‡ State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, CAS. 345 Lingling Road, Shanghai 200032, PR China S Supporting Information *

ABSTRACT: An easy two-step, one-pot synthesis of halogenated trifluoromethylated pyrroles is realized by sequential intermolecular hydroamination reaction of 2-trifluoromethyl-1,3-enynes with aliphatic primary amines under mild reaction conditions, and NXS mediated oxidative cyclization of the hydroamination product. The salient features of this method include mild conditions, readily available starting materials, general substrate scope, high efficiency and synthetic utility of the products.

T

knowledge, direct construction of pyrroles ring bearing both trifluoromethyl group and halogen atoms is rare. Very recently, we reported a silver-catalyzed tandem intermolecular and intramolecular hydroamination reaction of 2-trifluoromethyl-1,3-enynes7 with primary amines, delivering various ring-trifluoromethylated 3-pyrrolines in good yields (Scheme 1).8 During our mechanistic insight into this tandem

he halogenated pyrrole ring is a pivotal structural unit of many pharmacologically active natural products, bioactive molecules, and organic building blocks in organic synthesis (some examples are depicted in Figure 1).1 Thus, it is not

Scheme 1. Silver-Catalyzed Synthesis of RingTrifluoromethylated 3-Pyrrolines

Figure 1. Halogenated pyrrole-containing natural products.

surprising that various synthetic methods have been developed. Apart from the classical protocol, aromatic electrophilic halogenation of pyrrole ring with halogenating agents,1d,2 halogenating agents-mediated electrophilic cyclization/oxidation of homopropargylic amides3 or cycloisomerization of propargylic aziridines4 have been developed as efficient methods for the synthesis of halogenated pyrroles. On the other hand, the development of a methodology for the synthesis of heterocyclic compounds bearing a trifluoromethyl or perfluoroalkyl group has received much attention recently since the introduction of these groups in organic molecules often improves their biological activities for medicines and agrochemicals.5 In this context, substantial attention has been paid to the development of efficient methods for the synthesis of ring-trifluoromethylated or ring-fluorinated pyrroles.6 However, to the best of our © 2017 American Chemical Society

reaction, we found that treatment of enyne 1a with benzylamine 2a (2.0 equiv) in chlorobenzene at room temperature in the absence of AgNO3 catalyst for 45 h, both allenyl amine 3aa and homopropargylic amine 4aa were obtained in 41% and 26% isolated yield, respectively, along with recovery 28% of enyne 1a (eq 1). It is noteworthy that the homopropargylic amine 4aa could not undergo isomerization to allenyl amine 3aa under basic conditions. These two amine products have aroused our interest. We envisioned that halogenated 3-pyrrolines 5 or 2-pyrrolines 6 might be obtained by reacting with halogenating agents such as Received: August 9, 2017 Published: September 1, 2017 4968

DOI: 10.1021/acs.orglett.7b02427 Org. Lett. 2017, 19, 4968−4971

Letter

Organic Letters

could be delivered in 86% isolated yield upon treatment of monobromopyrrole 9aa with 2.0 equiv of NBS in MeOH (eq 3). Interestingly, upon treatment of iodopyrrole 7aa with 2.0 equiv of NBS in MeOH, iodine bromine exchange was observed and two inseparable compounds iodobromopyrrole 10aa and dibromopyrrole 8aa are formed, which was confirmed by GCMS analysis. The ratio of two compounds formed depended on reaction time (eq 4). On the basis of the above results, to avoid the tedious separation of the first step hydroamination products, allenyl amine and homopropargylic amine, and also to improve the overall operational efficiency, we probed whether the first hydroamination step and the subsequent NXS mediated electrophilic cyclization/oxidation could be combined in a onepot process. Considering that both allenyl amine 3aa and homopropargylic amine 4aa could be converted into the halogenated pyrrole by NXS in MeOH, first, we investigated the hydroamination reaction of enyne 1a and benzylamine 2a in MeOH. In order to improve the efficiency of hydroamination, increasing the amount of benzylamine 2a was necessary. To our delight, enyne 1a could be consumed completely when the reaction was carried out at room temperature for 12 h by using 3 equiv of benzylamine 2a, delivering 80% of homopropargylic amine 4aa as the predominant product determined by NMR analysis of crude product. Subjection of 4 equiv of NIS or NBS to the reaction mixture at room temperature would afford iodopyrrole 7aa or dibromopyrrole 8aa in 87%, 77% isolated yield, respectively (Scheme 3). Molecular iodine could also promote oxidative cyclization step, but gave iodopyrrole 7aa in

NXS, respectively, through an electrophilic cyclization process, and their further aromatization would offer a facile access to halogenated trifluoromethylated pyrroles 7 (Scheme 2). Herein we wish to report an easy two-step, one-pot construction of halogenated trifluoromethylated pyrroles through NXS (X = Br, I) mediated cascade. Scheme 2. Projected Reaction for Synthesis of Halopyrrole

In order to validate our hypothesis, N-iodosuccinimide (NIS) was first used as electrophilic cyclization reagent to react with allenyl amine 3aa and homopropargylic amine 4aa, respectively. To our delight, trifluoromethylated iodopyrrole 7aa was indeed formed in 81%, 85% isolated yield, respectively, when reaction was carried out with 3 equiv of NIS in MeOH at room temperature for 5 h (eq 2). However, under identical reaction

Scheme 3. One-Pot Synthesis of Halogenated Trifluoromethylated Pyrroles from Various 2Trifluoromethyl-1,3-enynes 1

conditions, the replacement of N-iodosuccinimide (NIS) with Nbromosuccinimide (NBS) led to trifluoromethylated dibromopyrrole 8aa in 75% isolated yield, along with monobromopyrrole 9aa in 10% isolated yield (eq 3). Increasing the amount of NBS to 4 equiv results in the quantitative yield of dibromopyrrole 8aa. The results indicated that dibromopyrrole 8aa might be derived from monobromopyrrole 9aa. Indeed, dibromopyrrole 8aa 4969


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Organic Letters

dibromopyrrole 8al was obtained in only 41% isolated yield when NBS was used instead of NIS. As in the case of furan-2ylmethanamine with NBS reaction partner, no dibromopyrrole 8ak could be obtained, although the first intermolecular hydroamination works smoothly, the detailed reason is unclear. (4) Chiral amine such as tert-butyl-2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl) acetate, a key intermediate of atorvastatin, was also tolerated, and novel potent pyrrolebased HMG-COA reductase inhibitors intermediates 7am, 8am could be constructed in 52% and 72% isolated yield, respectively.9 Obviously, the halogen atoms on the pyrrole ring provide handle for further elaborations to enrich stains family for drug screening. To explore the potential application, synthetic transformation of representative products 7aa was showcased in Scheme 5. The

79% isolated yield. With the established one-pot process, we then investigated the reaction scope by variation of two reaction components. The scope of readily available 2-trifluoromethyl1,3-enyne 1 was first examined. In general, enynes possessing different aryl groups on the alkyne moiety are suitable, affording halogenated pyrroles in good yields except enyne bearing an cyanophenyl ring on the alkyne moiety (iodopyrrole 7ha in 50% isolated yield, and dibromopyrrole 8ha in 46% isolated yield). However, the average yield for each step is still >67%, indicating this one-pot reaction strategy enhanced the reaction efficiency. Next, the scope of aliphatic primary amines toward this onepot, two-step reaction was investigated (Scheme 4). Several Scheme 4. One-Pot Synthesis of Halogenated Trifluoromethylated Pyrroles from Different Aliphatic Primary Amines 2

Scheme 5. Sequential Cross-Coupling to Construct Pentasubstituted Pyrrole 13 with Five Different Substituents

sequential cross coupling was designed to construct trifluomethylated triaryl substituted pyrrole. The Suzuki−Miyaura coupling of 7aa with p-tolylboronic acid afforded the diaryl substituted pyrrole 11 in 70% isolated yield. Subsequent treatment of 11 with 2 equiv of NBS in acetonitrile at room temperature, afforded bromopyrrole 12 in 77% isolated yield. Further Suzuki−Miyaura coupling with (4-methoxyphenyl)boronic acid offers trifluomethylated triaryl substituted pyrrole 13 in 55% isolated yield. It is well-known that polyaryl substituted pyrroles show the unique optical and electronic property.10 Indeed, pyrrole 13 exhibited aggregation-induced emission (AIE) behavior in a solution of water-MeOH when the concentration was increased (Figure 2). The results show the potential application of 13 and its analogues in the field of material science. In summary, we have developed a facile two-step, one-pot method for the synthesis of a range of halogenated trifluoromethylated pyrroles from 2-trifluoromethyl-1,3-enynes, readily aliphatic primary amines and halogenating agents such as NBS and NIS. By variation of the halogenating agents, ring trifluoromethylated monoiodo pyrrole or dibromo pyrrole skeletons can be readily accessed in moderate to good yields. This two-step, one-pot method employs a key halogenatingagents mediating step to trigger a cascade process featuring an initial electrophilic cyclization of the first intermolecular hydroamination product.

points are noteworthy: (1) The substituted benzylamines bearing electron-withdrawing or electron-donating groups on phenyl ring were all tolerant, affording the corresponding iodopyrroles 7ab−7ag and dibromopyrroles 8ab−8ag in moderate to good yields (2) This one-pot, two-step reaction also permitted the use of other aliphatic amines such as 1- or 2phenylethanamines and isopropylamine, furnishing the corresponding iodopyrroles 7ah−7aj in 69% to 78% yields and dibromopyrrole 8ah−8aj in 44%−60% yields. (3) The reaction of enyne 1a with aliphatic primary amines containing heteroaryl moieties such as furan-2-ylmethanamine, thiophen-2-ylmethanamine works smoothly with NIS, but it does not work well with NBS. For example, when thiophen-2-ylmethanamine and NIS were used as reaction partner, this one-pot, two-step reaction affords iodopyrrole 7al in 79% isolated yield, however, 4970


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Chinthalapudi, K.; Manstein, D. J.; Gutzeit, H. O.; Knölker, H.-J. Eur. J. Org. Chem. 2014, 2014, 4487. (3) (a) Knight, D. W.; Redfern, A. L.; Gilmore, J. Chem. Commun. 1998, 2207. (b) Knight, D. W.; Rost, H. C.; Sharland, C. M.; Singkhonrat, J. Tetrahedron Lett. 2007, 48, 7906. (c) Knight, D. W.; Redfern, A. L.; Gilmore, J. J. Chem. Soc., Perkin Trans. 1 2002, 622. (d) Okitsu, T.; Yumitate, S.; Sato, K.; In, Y.; Wada, A. Chem. - Eur. J. 2013, 19, 4992. (4) Yoshida, M.; Easmin, S.; Al-Amin, M.; Hirai, Y.; Shishido, K. Tetrahedron 2011, 67, 3194. (5) Petrov, V. A. Fluorinated Heterocyclic Compounds: Synthesis, Chemistry, and Applications; John Wiley & Sons: Hoboken, NJ, 2009. (6) For a review of ring-trifluoromethylated pyrroles and ringfluorinated pyrroles, please see: (a) Fujita, T.; Ichikawa, J. Heterocycles 2017, 95, 694. (b) Muzalevskiy, V. M.; Shastin, A. V.; Balenkova, E. S.; Haufe, G.; Nenajdenko, V. G. Synthesis 2009, 23, 3905. For selected examples: (c) Saijo, R.; Hagimoto, Y.; Kawase, M. Org. Lett. 2010, 12, 4776. (d) Kino, T.; Nagase, Y.; Ohtsuka, Y.; Yamamoto, K.; Uraguchi, D.; Tokuhisa, K.; Yamakawa, T. J. Fluorine Chem. 2010, 131, 98. (e) Wiehn, M. S.; Vinogradova, E. V.; Togni, A. J. Fluorine Chem. 2010, 131, 951. (f) Saijo, R.; Kawase, M. Tetrahedron Lett. 2012, 53, 2782. (g) Zeng, Q.; Zhang, L.; Yang, J.; Xu, B.; Xiao, Y.; Zhang, J. Chem. Commun. 2014, 50, 4203. (7) For examples using 2-trifluoromethyl-1,3-enynes as building blocks, please see: (a) Trost, B. M.; Debien, L. J. Am. Chem. Soc. 2015, 137, 11606. (b) Zatolochnaya, O. V.; Gevorgyan, V. Org. Lett. 2013, 15, 2562. (c) Hwang, J. H.; Jung, Y. H.; Hong, Y. Y.; Jeon, S. L.; Jeong, I. H. J. Fluorine Chem. 2011, 132, 1227. (d) Zhang, L.; Zeng, Q.; Mao, A.; Wu, Z.; Luo, T.; Xiao, Y.; Zhang, J. Org. Biomol. Chem. 2014, 12, 8942. (e) Yang, J.; Zhou, X.; Zeng, Y.; Huang, C.; Xiao, Y.; Zhang, J. Org. Biomol. Chem. 2017, 15, 2253. (8) Zhou, X.; Huang, C.; Zeng, Y.; Xiong, J.; Xiao, Y.; Zhang, J. Chem. Commun. 2017, 53, 1084. (9) Lopchuk, J. M.; Gribble, G. W. Tetrahedron Lett. 2015, 56, 3208. (10) Tong, B.; Dong, Y. Aggregation-Induced Emission and Applications of Aryl-Substituted Pyrrole Derivatives. In AggregationInduced Emission: Fundamentals and Applications; Qin, A., Tang, B., Eds.; John Wiley and Sons Ltd.: Chichester, U.K., 2013; Vol. 2, pp 131−156.

Figure 2. PL spectra of 13 in MeOH/water mixtures with different volumetric fractions of water (fw, vol %).

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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.7b02427. Descriptions of experimental procedures for compounds and analytical characterization (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Lu Liu: 0000-0003-2151-891X Yuanjing Xiao: 0000-0002-0185-1961 Junliang Zhang: 0000-0002-4636-2846 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to 973 Programs (2015CB856600), the National Natural Science Foundation of China (21372084, 21425205), STCSM (17ZR1408800) and Changjiang Scholars and Innovative Research Team in University (PCSIRT) for financial supports.

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REFERENCES

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A One-Pot Construction of Halogenated Trifluoromethylated Pyrroles

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