A Rhodium-Catalyzed [3 + 2] Annulation of General Aromatic

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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A Rhodium-Catalyzed [3 + 2] Annulation of General Aromatic Aldimines/Ketimines and N-Substituted Maleimides Chengfeng Zhu,† Jichao Luan,† Jun Fang, Xu Zhao, Xiang Wu, Yougui Li, and Yunfei Luo* Anhui Province Key Laboratory of Advanced Catalytic Materials and Reaction Engineering, School of Chemistry and Chemical Engineering, Hefei University of Technology, Hefei, 230009, China

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S Supporting Information *

ABSTRACT: A new class of rhodium-catalyzed, C−H activation triggered [3 + 2] annulations of aromatic aldimines or ketimines and maleimides was reported in this study. A broad scope of general imines without electron-withdrawing groups were successfully activated and could effectively react with N-substituted maleimide to afford pericyclic, multichiral centered amines in good yields and with excellent diastereoselectivity.

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Scheme 1. Transition Metals Catalyzed [3 + 2] Annulations of Imines and Electron-Deficient Olefins

ycloaddition and annulation reactions have long received much interest, and significant progress has been achieved due to their widely synthetic applications in broad research areas such as organic synthesis,1 material science, and biology.2 C−H activation,3 an emerging synthetic strategy which tackles the C−H bond of substrates without prefunctionalization, has been implanted in annulation reactions,4 and particularly intense effort has been made on the [3 + 2] annulation5−9 reactions in which aromatic imine substrates were used to yield synthetically useful indanyl/indenyl amine or amide5−8 (see Scheme 1). Quite a few successful protocols including enantioselective versions8 have been reported. However, C− H activation triggered [3 + 2] annulation reactions are still in their infancy in terms of synthetic applications due to the limitations in both substrates and electrophiles, which usually have to be provided with high reactivity. For example, active aromatic ketimines bearing electron-withdrawing groups, such as phosphonyl,5q acyl,5s or sulfonyl7 groups and highly reactive alkynes5j,m,l,p,8b or allenes,8a8c are the most used combinations of substrates and electrophiles in these types of reactions. Incorporation of both general imine substrates without an activating group and active olefins into this protocol remains underexplored. The only example was reported by Ackerman’s group, in which general aromatic ketimines and acrylates underwent [3 + 2] annulations in the presence of a manganese catalyst.6 Interestingly, aldimines, the less hindered substrates, appeared to be a challenge in this [3 + 2] annulation reaction.6,10 Most recently, Kim’s group demonstrated that aldimines having a tosyl group and electron-deficient olefins could be effectively catalyzed by a cationic rhodium catalyst to form a [3 + 2] annulation product (see Scheme 1).7 Herein, we report a new class of rhodium-catalyzed, C−H activation initiated [3 + 2] annulation reactions, in which a broad scope of general aromatic ketimines and aldimines were © XXXX American Chemical Society

effectively utilized as substrates and maleimides bearing an active CC double bond as electrophiles. Aiming to develop a [3 + 2] annulation of general imines and active olefins, our study commenced with a very stable cyclic ketimine 1, in which a heterocyclic structure of 2Hbenzo[b][1,4]oxazine was featured, and maleimide 2 to investigate the reaction. We found that the reaction only worked with Cp*RhCl2 and a copper acetate system after a Received: August 21, 2018

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DOI: 10.1021/acs.orglett.8b02671 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 2. Scope of Cyclic Ketimines and Maleimidesa,b

a

The reactions were carried out with the following conditions: 0.30 mmol of 1 and 0.36 mmol of 2 in the presence of 2.5 mol % Cp*RhCl2 dimer and 20 mol % copper acetate in 2.0 mL of solvent stirred at 50 °C for 15 h. bAll the yields are isolated yields. c200 mol % copper acetate, 2.5 equiv of maleimides, and 70 °C of reaction temperature were applied to the reaction.

protocol is compatible with this type of substrate, although the yield dropped apparently compared with that obtained on substrate 3. It was found that an increase of the copper acetate loading could promote the yields to some extent. The final optimal usage of copper acetate for the acyclic ketimines is 2.0 equiv, and the results are shown in Scheme 3. Initially, phenylacetone ketimine 4a was examined with various N-substituted maleimides and provided the desired products in moderate yields of 57−75% (see 5aa−5ah, Scheme 3). The drop in yields sometimes comes from the decomposition of substrates. Later, the scope of acyclic ketimines was examined and the result shows that the methodology is general to various aryl ketimines. A single diastereoisomer of products was formed smoothly, and the yields range from moderate to good (5bc−5db, Scheme 3). Importantly, it should be highlighted that ketimine (5c), generated from 2-naphthyl ketone and which could yield regioisomers,6 gave the single regioisomer (see 5cb and 5cc) and diastereoisomer product. This is probably due to the mild reaction temperature. This novel result significantly increases its potential usage in synthetic chemistry. When there was a meta substituting group in the substrate (5d), the activation site of arene exclusively went to the less hindered position that is opposite to the substituting group (5dc and 5db). This result is consistent with the selectivity of metalation that is reported in the literature.11 As the α-branched chiral amines possess a large percentage of core structures in drugs and natural products, it is important that aldimines could be adapted to this protocol. However, aldimines, which are less hindered than ketimines and are

combinatorial screen of different metal catalysts, solvents, and additives (see Supporting Information (SI) for details). With the optimal conditions in hand, the substrate scopes of cyclic ketimines (1a−j) were examined with maleimides having three representative N-substituents of hydride, alkyl, and aryl groups (2a−d, see Scheme 2). The results show that this new methodology generally workes with 2-aryl-2H-benzo[b][1,4]oxazine type ketimine substrates, which could undergo [3 + 2] annulations with N-H, N-Me, and N-aryl substituted maleimides smoothly to afford products 3 in good yields (51−88%) and with excellent diastereoselectivity (the relative configuration was confirmed by single-crystal diffraction on 3aa). According to the result shown in Scheme 2, the electrondonating group generally benefits from the reactions and gave a relatively better yield while the electron-withdrawing group has the opposite effect. For example, substrates 1b, 1d, and 1j, in which each or both aromatic rings of the benzoxazine structure has/have methyl groups, could afford the corresponding products in better yields (81% of 3bc, 78% of 3db, and 81% of 3jc) than that of the unsubstituted substrates 1a and halogenated substrates 1e, 1f, and 1g (52% of 3ac, 57% of 3ec, 62% of 3fa, and 51% of 3gc). Moreover, for these less active substrates, sometimes an increased copper acetate loading and a higher temperature were applied to achieve a moderate yield (3cb and 3gc). The impact of N-substituting groups of the maleimide to the reactions is not obvious. To explore the generality of this methodology, PMP group protected acyclic ketimines 4a−d were prepared and tested with the same conditions. We were pleased to find that this B

DOI: 10.1021/acs.orglett.8b02671 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 3. [3 + 2] Annulation of Acyclic Ketimines and NSubstituted Maleimidesa,b

Scheme 4. [3 + 2] Annulation of Acyclic Ketimines and NSubstituted Maleimidesa,b

a

The reaction was carried out with the same conditions as those used in Scheme 3. bAll yields were isolated yields. cCombined yield of two regioisomers.11

Scheme 5. Stoichiometric Reactions of the Rhodacycle a

The reaction was carried out with the following conditions: 0.30 mmol of 4 and 0.36 mmol of 2 in the presence of 5.0 mol % Cp*RhCl2 dimer and 200 mol % copper acetate in 2.0 mL of solvent stirred at 50 °C for 15 h. bAll yields were isolated yields.

supposed to be the least challenging substrates, have turned out to be problematic in this type of reaction, for a β-hydride elimination would occur to generate the CN double bond again.10 Gratifyingly, this protocol is also applicable to aromatic aldimines (6a−e), affording the desired products in good yields (61−85%) with excellent regio- and diastereoselectivity (Scheme 4). An exception was 6f, from which a pair of inseparable regioisomers in a ratio of 5:1 was obtained. This could be attributed to the fact that the meta-fluoro group could not differentiate the two possible sites significantly.11 The 2naphthyl substituted aldimine substrate yielded single regioisomer products (7ba and 7bb) similar to its ketimine analogs (5cb and 5cc in Scheme 4). This success again makes this protocol synthetically useful. Moreover, to the best of our knowledge, there is no literature precedent for the rhodiumcatalyzed [3 + 2] annulations of aldimines having no electronwithdrawing groups and electron-deficient olefins. Interestingly, a straightforward insertion of the unsaturated bond of the electrophiles into the rhodium−carbon bond of the rhodacycle complex, the most commonly proposed carborhodation step,5j,m,n,p,9d is unlikely to occur in this reaction system according to the results of stoichiometric reactions of the rhodacycle 8 and maleimide 2b (eq 1, Scheme 5). The reaction only proceeded when extra imine substrate

was present in the reaction.12 An unprecedented metathesis reaction of the rhodacycle 8a and free imine 6b (eq 2, Scheme 5), which could only occur with the presence of copper acetate, afforded the rhodacycle 9, suggesting that extra imine substrate along with copper acetate played a very crucial role in the carborhodation step in the reaction.12 In summary, we have developed a [3 + 2] annulation reaction of aromatic imine substrates and maleimides via a rhodium catalyzed C−H activation strategy. This protocol is applicable to a broad scope of imines including cyclic/acyclic ketimines and aldimines, in which an activation moiety such as an acyl or a sulfonyl group was not required. The wide substrate scope along with good yields and high diasteroselectivity make this protocol synthetically attractive. Further studies in regard to the reaction mechanism and new reactions relative to this reaction are currently ongoing in our laboratory. C

DOI: 10.1021/acs.orglett.8b02671 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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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.8b02671. Experimental procedures, compounds data, and spectra (PDF) Accession Codes

CCDC 1863180−1863182 contain 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: yunfl[email protected]. ORCID

Chengfeng Zhu: 0000-0002-9676-6750 Xiang Wu: 0000-0001-5428-9063 Yunfei Luo: 0000-0001-9366-118X Author Contributions †

C.Z. and J.L. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank Hefei University of Technology and the NSFC (Project Nos. 21401037 and 21672049) for financial support for this work. Y.L. thanks Prof. Jianliang Xiao at the University of Livperool in the U.K. for the key suggestions of rhodium chemistry and Prof. George O’Doherty at Northeastern University in Boston for valuable discussions.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b02671 Org. Lett. XXXX, XXX, XXX−XXX