Letter Cite This: Org. Lett. 2018, 20, 146−149
pubs.acs.org/OrgLett
Assembly of Diverse Spirocyclic Pyrrolidines via Transient Directing Group Enabled Ortho-C(sp2)−H Alkylation of Benzaldehydes Feng Li,†,§ Yirong Zhou,†,‡,§ Heng Yang,† Dandan Liu,† Bing Sun,† and Fang-Lin Zhang*,† †
School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan 430070, P. R. China Key Laboratory of Functional Small Organic Molecules, Ministry of Education, College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, P. R. China
‡
S Supporting Information *
ABSTRACT: A diversity-oriented synthesis of useful spirocyclic pyrrolidines was successfully accomplished via late-stage cascade reactions of o-succinimide-substituted benzaldehydes. A catalytic amount of aniline as a transient directing group was efficient for the ruthenium-catalyzed ortho-C(sp2)−H alkylation of benzaldehyde with maleimide. The in situ formed imine overrided a series of other traditional directing groups with excellent site selectivities. More importantly, only 0.5 mol % of ruthenium catalyst was sufficient for a 100 mmol scale-up reaction without column chromatography purification.
T
he azaspirocycles, especially spirocyclic pyrrolidines, are privileged core structures for constructing a wide range of natural products and useful drug molecules, which display a broad spectrum of biological and pharmacological activities (Figure 1).1 However, the reported synthetic methods either
Figure 2. Synthetic strategies toward spirocyclic pyrrolidines.
to provide ortho-functionalized benzaldehyde product; however, only a few reports mentioned this strategy hitherto.5 Especially when benzaldehyde bears other directing groups, the reaction usually cannot occur on the ortho-position of aldehyde due to the poorer coordination ability of the aldehyde group (Figure 2b).5d,6 The general solution is to transfer the aldehyde group into imine or oxime and then release the aldehyde through hydrolysis after completion of the C−H functionalization.7 The covalent installation and removal of the stoichiometric directing groups have significantly diminished the atom- and stepeconomy as well as the practical applications. Taking advantage of the transient directing group strategy in omitting these
Figure 1. Selected examples of biologically active spirocyclic pyrrolidines.
require excess steps1 or suffer a limitation on the variety of spirocyclic products available via a single method.2 It is therefore of great importance to develop a diversity-oriented synthesis3 strategy to access this type of valuable spiro heterocyclic compounds. We envisioned that o-succinimide-substituted benzaldehyde is a versatile bifunctional intermediate platform for various latestage transformations to rapidly prepare diverse spiro heterocycles (Figure 2a). Transition-metal-catalyzed direct C−H activation4 of benzaldehyde is the most efficient and direct way © 2017 American Chemical Society
Received: November 11, 2017 Published: December 19, 2017 146
DOI: 10.1021/acs.orglett.7b03502 Org. Lett. 2018, 20, 146−149
Letter
Organic Letters
Scheme 2. Substrate Scope Bearing Directing Groupsa,b
drawbacks,8 Yu’s group and we reported a diverse set of palladium (or iridium)-catalyzed ortho-C(sp2)−H functionalizations of benzaldehydes using transient directing groups which overrode a wide range of other coordinating functional groups present within the benzaldehydes (Figure 2c).9 In addition, our group mainly focused on the synthesis of heterocycles through cascade reactions.10 Herein, we report the first transient directing group enabled ruthenium-catalyzed ortho-C(sp2)−H alkylation of benzaldehydes with maleimides11 and subsequent diversityoriented synthesis of diverse novel spirocyclic pyrrolidines (Figure 2c). Ruthenium-catalyzed direct ortho-C(sp2)−H alkylation of para-ester-substituted benzaldehyde 1a with N-Et maleimide 2a was chosen for initial experiments (Scheme 1). Preliminary Scheme 1. Transient Directing Group Screeninga,b
a The reactions were carried out on 0.1 mmol scale of benzaldehyde 1a with maleimide 2a (1.5 equiv) in the presence of Ru(p-cymene)Cl2]2 (5 mol %), TDG (20 mol %), AgSbF6 (20 mol %), and 4chlorobenzoic acid (50 mol %) in a mixture solvent of DCE/HFIP = 5:1 (0.5 mL) at 60 °C for 24 h. bIsolated yield. a
trials showed that no desired product was detected in the case of bifunctional amino acids T1 and T2 as bidentate coordinating groups. Then, a series of anilines were evaluated as monodentate transient directing groups. To our delight, the anilines could deliver the expected product 3aa with exquisite site-selectivity. The electronic nature and positions of the substituent on the anilines exerted significant influence on the reaction because it affected the reversible imine formation process. After extensive ligand screening, T6 proved to be the most promising one which generated the highest isolated yield of 80%. The control experiments showed that no expected product was noticed in the absence of T6, which highlights the importance of this transient directing group strategy. The acid additive and reaction media also had evident influence on the transformation.12 With the optimized reaction conditions in hand, the generality of this ruthenium catalytic system was investigated. As shown in Scheme 2, a variety of benzaldehydes bearing different coordinating functional groups provided the corresponding osuccinimide-substituted benzaldehydes in good yields. The in situ transiently formed imine could override a wide range of functional moieties which are normally used as ortho-directing groups for various transition-metal-catalyzed C−H activations, including ester (3aa and 3ka), carbonyl acid (3ba), sulfone (3ca), amide (3da and 3ia), carbamate (3ea and 3ja), phenol (3fa), sulfonamide (3ga), and ketone (3ha), etc. It is noteworthy that product (3la) owning a fluorescent moiety may be potentially applied in material chemistry.13 Furthermore, the application of our method to the late-stage diversification of pharmaceutical molecules containing multiple coordinating sites was successfully developed. In case of a celecoxib analogue, good yield and complete site selectivity were achieved (3ma). The results indicated that the transient directing group could override not only the sulfonamide group but also the pyrrazole
Under the same conditions as in Scheme 1. bIsolated yield.
heterocycle. Finally, natural amino acid or chiral acid (ibuprofen and ketoprofen) derived substrates were also able to generate good yield (3na−pa). Next, the reaction scope was extended to more general benzaldehyde substrates, and the results are depicted in Scheme 3. In general, an extremely broad substrate scope was explored with good to high yields. A variety of halogen atoms, even iodine (5ja), were well tolerated, which permit valuable opportunities for various late-stage derivatizations. The steric hindrance exhibited little effect on the outcomes; all of the ortho-, meta-, or para-substituted benzaldehydes could react well with maleimides (5aa−ga vs 5ha−na vs 5oa−sa). On the other hand, the electronic properties did not possess any evident influence for the reaction. No matter whether the substrates contain strong electron-donating groups or -withdrawing moieties, all of them proved to be suitable coupling partners (5da, 5ea, and 5la vs 5fa, 5ga, and 5ma). Larger conjugated systems (5ta, 5ua, and 5va) were also compatible and generated the expected products with high efficiency. Finally, a range of maleimides with different substitutes on nitrogen atom were investigated (5cb−cj). Unsubstituted maleimide (5cb) provided moderate efficiency, while the others gave good yields. More importantly, the free alcohol (5ci) and acid (5cj) were also well tolerated. In light of previous reports,8m−o,11a a possible mechanism is proposed in Scheme 4. First, benzaldehyde condenses with T6 to form imine A. By treatment of silver salt, ruthenium dimer catalyst delivers the active species B. Subsequently, the orthoC(sp2)−H activation of benzaldehyde leads to the formation of the key metallacycle C. Then, coordination of 2a and subsequent alkene migratory insertion provide seven-membered intermedi147
DOI: 10.1021/acs.orglett.7b03502 Org. Lett. 2018, 20, 146−149
Letter
Organic Letters Scheme 3. Substrate Scope Investigationa,b
a
Scheme 5. Gram-Scale Preparation of 5sa and Its Diverse Derivations
Under the same conditions as in Scheme 1. bIsolated yield.
Scheme 4. Proposed Mechanism
of novel useful spiro heterocycles through diverse late-stage transformations. In the presence of copper catalyst, 5sa could be oxidized to generate a spiro lactone 6. The Michael addition− Henry dehydration cascade reaction with nitroolefin provided a novel spiro-fused tricycle 7. Via treatment of 5sa with aldehyde, spiro hemiacetal was obtained, which could further be oxidized to deliver the corresponding lactone (8−11). On the other hand, the hydroxyl group of hemiacetal could be easily removed by Et3SiH to yield ether 12. The reaction of 5sa with (phenylsulfonyl)-N-tosylmethanamine gave a good yield of amino hemiacetal 13. Intramolecular redox-Mannich reaction of 5sa with 1,2,3,4-tetrahydroisoquinoline (THIQ) led to the desired product 14 that contains the tetrahydroprotoberberine core.14 In conclusion, the first transient directing group enabled ruthenium-catalyzed ortho-C(sp2)−H alkylation of benzaldehydes with maleimides was successfully developed, featuring high atom economy and excellent functional group tolerance. Notably, the high efficiency and practicality of this method was demonstrated in an example of a 100 mmol scale reaction with only 0.5 mol % catalyst loading and simple purification of product without column chromatography. The in situ transiently formed imine through the reversible condensation proved to be a privileged directing group that could override a series of other traditional functional moieties with high site selectivities. Delightedly, diverse useful spiro heterocycles were efficiently constructed via the consecutive cascade reactions of the osuccinimide-substituted benzaldehyde. Further applications of this novel strategy in the preparation of other spiro heterocycles are underway in our laboratory.
ate E. The β-hydride elimination process is impossible due to the lack of syn-planar β-hydrogen atom with respect to the metal center. Therefore, protodemetalation by carboxylic acid allows the regeneration of the active catalyst B along with product F. To further explore the practicality of the current methodology, a 100 mmol scale reaction of 4s was carried out with 1.8 equiv of 2a. The expected product 5sa was obtained in 86% yield (22.23 g) after recrystallization from ethyl acetate without column chromatography purification (Scheme 5). It should be noted that only 0.5 mol % of ruthenium catalyst along with 7 mol % of directing group was sufficient for the completion of the transformations, which highlighted the high catalytic efficiency and practicability of this method. Considering that the orthosubstituted benzaldehyde is versatile bifunctional intermediate, the synthetic utility was demonstrated in preparation of a series 148
DOI: 10.1021/acs.orglett.7b03502 Org. Lett. 2018, 20, 146−149
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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.7b03502. Experimental details and spectra for important compounds including fluorescence profiles and NMR spectra (PDF) Accession Codes
CCDC 1558440, 1558443, and 1571910 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:
[email protected]. ORCID
Fang-Lin Zhang: 0000-0002-7472-9713 Author Contributions §
F.L. and Y.Z. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for financial support from the National Natural Science Foundation of China (no. 21602089). REFERENCES
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DOI: 10.1021/acs.orglett.7b03502 Org. Lett. 2018, 20, 146−149
