Amine-Controlled Divergent Reaction: Iminolactonization and

Letter pubs.acs.org/OrgLett

Amine-Controlled Divergent Reaction: Iminolactonization and Olefination in the Presence of a Cu(I) Catalyst Takashi Nishikata,* Kohei Itonaga, Norihiro Yamaguchi, and Michinori Sumimoto Graduate School of Science and Engineering, Yamaguchi University, Ube, Yamaguchi 755-8611, Japan S Supporting Information *

ABSTRACT: α-Bromoamides and styrenes underwent iminolactonization reactions (carbooxygenation), in which simultaneous C−C and C−O formation occurred in the presence of a copper catalyst with triethylamine as the base. Conversely, olefination reactions occurred in the presence of a Cu catalyst with piperidine as the base. The selectivities in those reactions were very high.

any chemists are interested in discovering unique reactions to either design strategic organic syntheses or shorten current synthetic routes of complex molecules. However, finding new reactions is difficult and often unpredictable. Therefore, some chemists use high-throughput methods to discover novel and unpredictable chemical reactions more quickly.1−3 Another approach to discover novel reactions is to control the reactivity of the intermediate by using a finely tuned catalytic system, in which divergent bond-forming steps occur under different conditions. This methodology allows for efficient access to diverse molecules from “one” molecule. Therefore, divergent processes have been of interest for many decades to develop controllable reaction pathways (Figure 1).4−6 In 2014, Oguri and co-workers accomplished the transformation of vinyl indole derivatives to diverse alkaloids through the control of five

M

types of reactivities of the vinyl indole derivatives.4 This is an ideal methodology for achieving molecular diversity. Recent related progress in this field includes controlling the properties of reactive intermediates, such as in C−H arylation reactions. Yang found that controlling the reactivities of active and inert C−H bonds enables C−H cyclization to give fused five- or three-membered rings.5a Gaunt achieved a regiodivergent C−H arylation, in which C3 or C2 arylation of indoles occurred selectively.5g Both of these divergent C−H transformations were predominantly controlled by solvent effects. Chang developed a Ru-catalyzed regiodivergent olefin hydrocarbamoylation reaction controlled by the addition of ammonium salts to give five- or six-membered rings.5c White reported that homoallylic urea underwent intramolecular N- vs O-cyclization by using a combination of a Pd catalyst and Lewis acid.5d The Tang and Shi group reported the ringexpansion reaction of functionalized cyclopropanes to give five- or four-membered rings, which was accomplished by the variation of the catalyst (Rh or Ru) to control CO insertion.5b The Luo group discovered the effects of an In(III) catalyst on 1,4- vs 1,2-additions of indoles to α,β-unsaturated ketoesters,5e where different In(III) salts activated either the β-carbon or carbonyl group in the α,βunsaturated ketoesters. As Wang reported, the reaction of a Michael acceptor and 2-bromomalonate ester produced cyclopropane via a Michael-induced ring closure (MIRC) reaction but the choice of added base caused the reaction to proceed through a Baylis−Hillman-like olefination, as opposed to a cyclopropanation.5f The control of product ring size is quite difficult when synthesizing medium-sized rings via migration reactions of diazo ketones. However, Stoltz discovered that the use of UV light or a silver(I) catalyst were very effective in controlling reactive intermediates to obtain fused seven- or five-membered rings from diazo ketones, respectively.5h As shown in Figure 1, research on divergent reactions mainly revolves around regiodivergent reactions,5c,g,6 where controlling

Figure 1. Recent selected substrates possessing reaction diversity.

Received: April 5, 2017 Published: May 10, 2017

© 2017 American Chemical Society

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DOI: 10.1021/acs.orglett.7b01020 Org. Lett. 2017, 19, 2686−2689

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Organic Letters Table 1. Optimizationsa

the chemoselectivities of substrates possessing two or more functional groups is very difficult. The difficulties of divergent methods include the choice of substrate and controlling the reactivity of intermediates through the use of catalysts, additives, or solvents. Thus, reports on the divergent reaction to synthesize diverse skeletons from one molecule with high selectivities are still rare and challenging. In this regard, we have focused on the reactivity of α-bromoamides (Br−RR′CCO[N]) (1) in the presence of olefins in order to exploit controllable reaction pathways for divergent reactions (Scheme 1). Compound 1 has Scheme 1. Carbo-oxygenation vs Olefination

two interesting reactive sites. The first is a Br−C bond, which is a good reactant for typical cross-coupling reactions, such as olefinations, in the presence of a transition metal catalyst. The second is the nucleophilic oxygen present in amides, which can undergo a carbooxygenation (iminolactonization) reaction to simultaneously form C−C and C−O bonds. Despite the extensive research regarding carbooxygenation reactions, methodologies to alter the tandem reaction pathways for C−C and C−O bond formations, which provide distinctly different products, have not yet been studied.7,8 We recently reported the reaction of styrenes and αbromoesters (Br−RR′CCO2R″) to afford tertiary-alkylative olefination products in good yields via atom-transfer radical addition (ATRA) followed by dehydrohalogenation in the presence of a copper catalyst, which is an efficient catalyst for alkylation reactions.9−12 However, α-bromoamides (Br− RR′CCO[N]) were not applicable to this reaction, in which the dehydrohalogenation of haloamides to acrylamide derivatives was the predominant reaction.9 During the course of our continuous study, we found that the reaction of α-bromoamides (1) and styrenes (2) afforded iminolactones (3) (carbooxygenation), which are not only good bioactive drug candidates13 but also generally very difficult to synthesize.14 Olefins (4) were also simultaneously synthesized via olefination in the presence of an amine and a copper catalyst (Scheme 1). Here we report that a switch between reaction pathways for carbooxygenation and olefination was induced by an amine in the presence of a copper catalyst. In the optimization studies, we used a combination of αbromoamide (1a, 1.5 equiv) and p-methylstyrene (2a, 1 equiv) in the presence of CuI (10 mol %), tris(2-pyridylmethyl)amine (TPMA, 5 mol %), BnBu3NBr (20 mol %), and amine in toluene under a nitrogen atmosphere at 100 °C (Table 1). In the absence of the catalyst, ligand, or amine, no reaction occurred; furthermore, yields were decreased in the absence of the ammonium salt because of the decreased solubility or the formation of active catalyst with ammonium.15 Reaction with iPr2NH and CyMe2NH gave a mixture of 3a and 4a; however, iminolactonization exclusively occurred with Cy2NH (runs 1−4). 1 and 2 equiv of Cy2NH gave 3a as the sole product, but this reason was unclear. Curiously, 1 equiv of Et3N gave 4a exclusively, but 2 equiv of Et3N provided a 99% yield of 3a with excellent

a Conducted at 100 °C for 20 h in toluene with 1 (1.0 equiv), 2 (1.5 equiv), CuI (10 mol %), TPMA (5 mol %), amine, and BnBu3NBr (20 mol %). The selectivities are determined by 1H NMR analysis of the crude mixture. bConducted at 50 °C. cConducted at room temperature.

selectivity (runs 5 and 6). We also tried 1.1 and 1.2 equiv of Et3N, and a mixture of 3a and 4a was obtained. The result with Et3N however encouraged us to switch carbooxygenation to olefination. Primary alkylamines, and strong bases, including DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) and DABCO (1,4-diazabicyclo[2.2.2]octane), resulted in low yields with moderate selectivities; however, tertiary amines, including Bu3N and Hex3N, gave excellent selectivities for the olefination leading to 4a (runs 7−12). Further improvements were obtained in the reaction with cyclic secondary amines, including morphorine and piperidine (runs 13 and 14). We also examined various catalysts (CuBr, CuCl, CuOAc, and CuBr2), solvents (hexane, 1,4-dioxane, DMF, and EtOH), and chlorinated substrate 1, but the results were poor. Interestingly, the reaction pathways depend on the reaction temperature or the concentration of added amine. For example, a 62% yield of 4a was obtained at 50 °C but the reaction at room temperature under the same conditions resulted in a 49% yield of 3a (runs 15 and 16). When 2 equiv of piperidine were used, a 64% yield of 3a was exclusively obtained (run 17). Iminolactonization and olefination are two distinctly different reactions, and reaction temperature and equivalents of the amines strongly affected the selectivities, although both reactions could be controlled by adding amines. As illustrated by several representative examples in Table 2, the scope of this divergent reaction is broad. α-Bromoamide derivatives 1 bearing various functional groups reacted smoothly with 2a to produce the corresponding products in good yields with switching between iminolactonization and olefination. αBromoamides possessing a tertiary- or secondary-alkyl moiety 2687

DOI: 10.1021/acs.orglett.7b01020 Org. Lett. 2017, 19, 2686−2689

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Organic Letters Table 2. Reactions with Bromoamides 1a

and 4g−j, substituents on the nitrogen did not affect the cyclization process. 1 possessing electron-donating or -withdrawing groups smoothly reacted with 2a in good to excellent yields with excellent selectivities. We next examined various styrene derivatives 2 (Table 3). Electron-deficient styrenes (2c and 2d) gave good to excellent Table 3. Reactions with Olefins 2a

a Conducted at 100 °C for 20 h in toluene with 1 (1.0 equiv), 2 (1.5 equiv), CuI (10 mol %), TPMA (5 mol %), amine, and BnBu3NBr (20 mol %). The selectivities are determined by 1H NMR analysis of the crude mixture. b2 equiv of Et3N were used. c1 equiv of piperidine was used. dConducted in DMF at 120 °C.

yields, and more electron-deficient styrene 2e possessing an ester group resulted in low to moderate yields, suggesting that the alkyl radicals generated in situ are slightly electrophilic. As was observed in both reactions, selectivities did not depend on the substituents on the alkenes, but reactivities decreased slightly in the case of reactions with electron-deficient alkenes. For example, styrenes possessing an electron-donating group (2b) gave good yields, but electron-deficient styrenes (2c−2e) gave moderate-togood yields (3n and 4l−4n). We are currently investigating the reaction mechanism, and some control experiments and DFT calculations for our expected mechanism are shown in the Supporting Information. An interesting phenomenon was also observed when acrylates 2f and 2g were employed as substrates (Scheme 2). Iminolactonization of 2f and 2g leading to 3o and 3p, respectively, occurred in the presence of iPr2NH; however, the corresponding olefination in the presence of piperidine did not occur. In this case, carboamidation products 5a and 5b were obtained instead of olefin 4. Controlling N and O nucleophilicity of an amide group is generally quite difficult;16 however, recent progress in this area has been accomplished by White and co-workers. They were able to successfully control the N and O nucleophilicity of a urea group

Conducted at 100 °C for 20 h in toluene with 1 (1.0 equiv), 2 (1.5 equiv), CuI (10 mol %), TPMA (5 mol %), amine, and BnBu3NBr (20 mol %). The selectivities are determined by 1H NMR analysis of the crude mixture. b2 equiv of Et3N were used. c1 equiv of piperidine was used. d2 equiv of Cy2NH were used. eConducted in DMF at 120 °C. a

(1b−f) reacted with 2a under each set of optimized conditions to give the desired products (3b−f and 4b−f) in yields ranging from 47% to 80%. In the case of 3c, 3e, and 3f, a mixture of diastereomers (1:1) is formed. In iminolactonization, the electron density of the nitrogen atom could be important for the nucleophilic attack of oxygen. According to the yields of 3g−j 2688

DOI: 10.1021/acs.orglett.7b01020 Org. Lett. 2017, 19, 2686−2689

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Organic Letters Scheme 2. O- vs N-Cyclization Leading to 3 or 5, Respectively (Carboamidation)

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by varying the Lewis acid used for the allylic functionalization of terminal olefins.5d According to the White group, N-cyclization proceeded via deprotonation of the amide and O-cyclization was promoted by the addition of an azaphilic Lewis acid, which hindered the nitrogen nucleophilic attack. However, these types of divergent cyclization reactions are still challenging and require the development of new methodologies. In this study, we found that the iminolactonization reaction (O-cyclization) leading to 3o and 3p could be changed to a carboamidation reaction (Ncyclization) leading to lactams 5a and 5b upon variation of the solvent (from toluene to N,N-dimethylformamide) and addition of an amine. In conclusion, the reaction of α-bromoamide 1 with styrene 2 provided a divergent reaction to produce iminolactone 3 or olefin 4 from the same starting material under different conditions. Iminolactonization took place in the presence of 2 equiv of an amine at room or high temperature, whereas olefination took place in the presence of 1 equiv of an amine at high temperature. These results not only suggest the efficient synthesis of iminolactone 3 and β,γ-unsaturated amide 4 but also suggest new uses of amines in copper-catalyzed radical reactions toward divergent processes.

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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.7b01020. Experimental procedures, spectroscopic data for all new compounds, and DFT calculation details (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Takashi Nishikata: 0000-0002-2659-4826 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support provided by a program to disseminate tenure tracking system, MEXT, Japan, and the UBE Foundation is gratefully acknowledged. We thank Prof. Dr. Kenji Hori (YU) and Dr. Shingo Ishikawa (YU) for helpful discussions.

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REFERENCES

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DOI: 10.1021/acs.orglett.7b01020 Org. Lett. 2017, 19, 2686−2689