Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Alkylation Reactions of Azodicarboxylate Esters with 4‑Alkyl-1,4Dihydropyridines under Catalyst-Free Conditions Kazunari Nakajima,*,† Yulin Zhang,‡ and Yoshiaki Nishibayashi*,‡ †
Frontier Research Center for Energy and Resources, School of Engineering, The University of Tokyo, Bunkyo-ku, Tokyo 113-8656, Japan ‡ Department of Systems Innovation, School of Engineering, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
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S Supporting Information *
ABSTRACT: Introduction of alkyl groups on azodicarboxylate esters is an important method to prepare alkyl amine derivatives. Herein, we report reactions of 4-alkyl-1,4-dihydropyridines as alkylation reagents with di-tert-butyl azodicarboxylate to prepare alkyl amine derivatives under heating conditions. The alkylation reactions via C−C bond cleavage of the dihydropyridines are achieved in the absence of catalysts and additives. Table 1. Optimization of Reaction Conditionsa
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zodicarboxylates are an important class of electrophilic amination reagents allowing C−N bond formation.1 Typically, nucleophilic attack of carbon-centered nucleophiles on azodicarboxylates produces the corresponding aminofunctionalized products. While, the involvement of radical species for C−N bond formation with azodicarboxylates has been known for decades; however, such examples have been relatively limited.1a,2 Recently, usage of a dihydropyridine framework, 4-alkyl-1,4dihydropyridines, as alkylation reagents has offered a variety of alkylation reactions under photochemical conditions.3,4 Previously, we reported photoredox-catalyzed aromatic substitution reactions of cyanoarenes with dihydropyridines, and nickel-/photoredox-catalyzed cross-coupling type alkylation reactions of aryl and alkenyl halides with dihydropyridines.3 In addition to the photochemical conditions, thermal conditions also allow utilization of 4-alkyl-1,4-dihydropyridines as alkylation reagents.5 To date, several reaction systems have been reported: Lewis acid-catalyzed alkylation of aldehydes and imines,5a,b substitution reactions of nitroalkenes with the use of radical initiators,5c and alkylation of nitrogen heterocycles with single electron oxidants.5d However, the synthetic applications of the dihydropyridines under photochemical and thermal conditions have been limited to C−C bond forming reactions. Based on the research background, we have envisaged reactions of dihydropyridines with azodicarboxylate to achieve C−N bond forming reaction. As a result, we found the reactions proceed under heating conditions in the absence of catalysts and additives. Herein, we report typical results of the present reaction system. At first, we investigated reactions of 4-benzyl-3,5-bis(ethoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridines (1a) with di-tert-butyl azodicarboxylate (2) as typical substrates (Table 1). The reaction of 1a with 2 in toluene was carried out at 80 °C for 18 h under dark, where the desired alkyl addition product was obtained (3a) in 90% yield (Table 1, entry 1). © XXXX American Chemical Society
entry
solvent
temp (°C)
yield of 3a (%)b
1 2 3 4 5 6 7 8c 9d
toluene toluene toluene DME 1,4-dixoane MeCN DMF toluene toluene
80 50 25 80 80 80 80 80 25
90 43 18 70 57 20 0 88 87
a
Reaction of 1a (0.250 mmol) with 2 (0.275 mmol) was carried out in various solvents at the indicated temperature for 18 h under dark to avoid ambient light, such as ceiling light. bIsolated yield. cIn the presence of benzoyl peroxide (0.025 mmol) as a radical initiator. dIn the presence of fac-Ir(ppy)3 (0.0025 mmol) as a photoredox catalyst under visible light illumination (14 W white LED).
Separately, we confirmed that no substantial effect was observed under ambient light, such as ceiling light. However, to avoid ambient light, we carried out the following all reactions under dark. When we investigated reactions at lower temperatures, the yields of 3a decreased unfortunately (Table 1, entries 2 and 3). Other solvents such as 1,2-dimethoxyethane (DME), 1,4-dioxane, MeCN, and DMF were also examined, but we found toluene was the best solvent (Table 1, entries 4−7). In addition, we confirmed that addition of 0.1 equiv of benzoyl peroxide as a radical initiator did not affect Received: May 1, 2019
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DOI: 10.1021/acs.orglett.9b01537 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters the yield (Table 1, entry 8). However, when we applied typical photoredox-catalyzed conditions using fac-Ir(ppy)3,3 the reaction proceeded at room temperature (Table 1, entry 9). As a result, we found that this alkylation reaction proceeds under both thermal and photochemical conditions, but we further investigated the simple heating conditions to avoid the use of unnecessary reagents. Next, we investigated the effect of electron-withdrawing groups in dihydropyridines (Scheme 1). Introduction of tertScheme 1. Effect of Electron-Withdrawing Groups
butyl ester moieties instead of ethyl ester moieties resulted in a similar yield of 3a, while introduction of methyl ester and cyano moieties gave lower yields of 3a. Based on these results, further experiments were carried out with dihydropyridines bearing ethyl ester moieties. Next, we explored the scope of alkyl substituents on dihydropyridines (Figure 1). Dihydropyridines bearing functionalized benzyl groups were successfully transformed into the corresponding products in high yields (3b−g). Simple alkyl groups such as methyl, ethyl, iso-butyl, nonyl, 2-phenylethyl, 2butyl, and cyclohexyl groups were available to give the corresponding products in good yields (3h−n). Sterically hindered diphenylmethyl group and 2-phenylprop-2-yl group were also examined, but only low to moderate yields of products were obtained in both cases (3o and 3p). In addition, alkyl groups bearing ester moiety and benzyloxy moiety were also introduced successfully (3q and 3r). Thus, we have successfully demonstrated applicability of a broad range of alkyl groups in the present reaction system. We also investigated a larger scale reaction of 1a (1.00 mmol) with 2 (1.10 mmol) in toluene under the typical reaction conditions (Scheme 2). As a result, the corresponding product 3a was obtained in 86% yield (277 mg). To obtain mechanistic insight, we examined the reaction of a dihydropyridine bearing a cyclopropylmethyl group as a radical clock (4) (Scheme 3).6 After the reaction, the corresponding ring opening-alkylation product (5) was observed as a sole product in 63% yield. This result clearly indicates the generation of alkyl radical in the present reaction system. Based on the possibility of radical mechanism, we anticipated that partial decomposition of the azodicarboxylate might generate some radical species. Actually, decomposition of an azodicarboxylate into dinitrogen and two acyl radicals under thermal conditions has been proposed for decades.1a When we investigated a reaction mixture of 1a and 2 in toluene-d8 as a solvent, we detected 2% yield of tert-butyl formate (HBoc) (Scheme 4). The generation of HBoc indicates that a small amount of 2 decomposes into dinitrogen and tert-butoxycarbonyl radicals, and the generated radical species induces a radical chain mechanism.
Figure 1. Reactions of various dihydropyridines. Reaction of dihydropyridines (1) (0.250 mmol) with 2 (0.275 mmol) was carried out in toluene at 80 °C for 18 h under dark to avoid ambient light, such as ceiling light. aNaOAc (0.500 mmol) was added. bIn DME at 110 °C. c4-(2-Phenylprop-2-yl)-3,5-dicyano-2,6-dimethyl-1,4-dihydropyridine was used as substrate in toluene 140 °C for 72 h.
Scheme 2. Larger Scale Reaction of 1a with 2
Scheme 3. Reaction of Cyclopropylmethyl Group
B
DOI: 10.1021/acs.orglett.9b01537 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 4. Observation of tert-Butyl Formate
into B produces the corresponding product 3 along with formation of A as a chain propagation process. In summary, we have achieved the first successful C−N bond forming reactions with dihydropyridines as alkylation reagents. The reaction proceeds without the use of any catalysts and additives under heating conditions. In this reaction system, we found the azodicarboxylate works as not only an amination reagent but also a radical initiator. We believe the present findings provide an insight into the design of new radical-type amination reactions.
Previously, Tang and co-workers reported alkylation reactions of nitroalkenes with dihydropyridines, which are induced by 2,2′-azobis(isobutyronitrile) (AIBN) as a radical initiator.5c In this reaction system, hydrogen atom abstraction from N−H moiety in the dihydropyridine generates Ncentered radical species, which undergo subsequent C−C bond cleavage to give the corresponding alkyl radical. We examined the reaction of N-methylated dihydropyridine (6) with 2 under the typical reaction conditions (Scheme 5).
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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.9b01537. Experimental details, additional discussion, spectroscopic data (PDF)
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Scheme 5. Reaction of N-Methyldihydropyridine (6)
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Kazunari Nakajima: 0000-0001-9892-5877 Yoshiaki Nishibayashi: 0000-0001-9739-9588 In this case, no corresponding product 3a was observed at all with quantitative recovery of 6. This result may indicate that the hydrogen atom abstraction from N−H moiety in the dihydropyridine is involved in the present reaction system. Based on these observations, a plausible reaction pathway is shown in Scheme 6. First, decomposition of 2 into dinitrogen
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work is supported by CREST, JST (JPMJCR1541). We thank Grants-in-Aid for Scientific Research (numbers JP17H01201, JP15H05798, JP18K19093, and 19K15556) from JSPS and MEXT.
Scheme 6. Plausible Reaction Pathway
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REFERENCES
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DOI: 10.1021/acs.orglett.9b01537 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters (3) (a) Nakajima, K.; Nojima, S.; Sakata, K.; Nishibayashi, Y. Visible-Light-Mediated Aromatic Substitution Reactions of Cyanoarenes with 4-Alkyl-1,4-dihydropyridines through Double Carbon− Carbon Bond Cleavage. ChemCatChem 2016, 8, 1028. (b) Nakajima, K.; Nojima, S.; Nishibayashi, Y. Nickel- and Photoredox-Catalyzed Cross-Coupling Reactions of Aryl Halides with 4-Alkyl-1,4dihydropyridines as Formal Nucleophilic Alkylation Reagents. Angew. Chem., Int. Ed. 2016, 55, 14106. (c) Nakajima, K.; Guo, X.; Nishibayashi, Y. Cross-Coupling Reactions of Alkenyl Halides with 4Benzyl-1,4- Dihydropyridines Associated with E to Z Isomerization under Nickel and Photoredox Catalysis. Chem. - Asian J. 2018, 13, 3653. (4) (a) Chen, W.; Liu, Z.; Tian, J.; Li, M.; Ma, J.; Cheng, X.; Li, G. Building Congested Ketone: Substituted Hantzsch Ester and Nitrile as Alkylation Reagents in Photoredox Catalysis. J. Am. Chem. Soc. 2016, 138, 12312. (b) Gutiérrez-Bonet, Á .; Tellis, J. C.; Matsui, J. K.; Vara, B. A.; Molander, G. A. 1,4-Dihydropyridines as Alkyl Radical Precursors: Introducing the Aldehyde Feedstock to Nickel/Photoredox Dual Catalysis. ACS Catal. 2016, 6, 8004. (c) Goti, G.; Bieszczad, B.; Vega-Peñaloza, A.; Melchiorre, P. Stereocontrolled Synthesis of 1,4-Dicarbonyl Compounds by Photochemical Organocatalytic Acyl Radical Addition to Enals. Angew. Chem., Int. Ed. 2019, 58, 1213. (d) Song, Z.-Y.; Zhang, C.-L.; Ye, S. Visible light promoted coupling of alkynyl bromides and Hantzsch esters for the synthesis of internal alkynes. Org. Biomol. Chem. 2019, 17, 181. (e) Wang, X.; Li, H.; Qiu, G.; Wu, J. Substituted Hantzsch esters as radical reservoirs with the insertion of sulfur dioxide under photoredox catalysis. Chem. Commun. 2019, 55, 2062. (f) Phelan, J. P.; Lang, S. B.; Sim, J.; Berritt, S.; Peat, A. J.; Billings, K.; Fan, L.; Molander, G. A. Open-Air Alkylation Reactions in Photoredox-Catalyzed DNA- Encoded Library Synthesis. J. Am. Chem. Soc. 2019, 141, 3723. (5) (a) Mashraqui, S. H.; Kellog, R. M. Pyridinium Salts Structurally Relaed to NAD(P)+ as Enolate Transfer Agents. J. Am. Chem. Soc. 1983, 105, 7792. (b) Li, G.; Chen, R.; Wu, L.; Fu, Q.; Zhang, X.; Tang, Z. Alkyl Transfer from C-C Cleavage. Angew. Chem., Int. Ed. 2013, 52, 8432. (c) Li, G.; Wu, L.; Lv, G.; Liu, H.; Fu, Q.; Zhang, X.; Tang, Z. Alkyl transfer from C−C cleavage: replacing the nitro group of nitro-olefins. Chem. Commun. 2014, 50, 6246. (d) Gutiérrez-Bonet, Á .; Remeur, C.; Matsui, J. K.; Molander, G. A. Late-Stage C−H Alkylation of Heterocycles and 1,4-Quinones via Oxidative Homolysis of 1,4-Dihydropyridines. J. Am. Chem. Soc. 2017, 139, 12251. (6) (a) Griller, D.; Ingold, K. U. Free-Radical Clocks. Acc. Chem. Res. 1980, 13, 317. (b) Newcomb, M. Competition Methods and Scales for Alkyl Radical Reaction Kinetics. Tetrahedron 1993, 49, 1151.
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DOI: 10.1021/acs.orglett.9b01537 Org. Lett. XXXX, XXX, XXX−XXX
