Letter pubs.acs.org/OrgLett
Intramolecular Aminoalkoxylation of Unfunctionalized Olefins via Intramolecular Iodoamination and Aziridinium Ion Ring-Opening Sequence Hui Sun, Bin Cui, Lili Duan,* and Yue-Ming Li* State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, People’s Republic of China S Supporting Information *
ABSTRACT: The preparation of prolinol ether type compounds was realized via MnI2-catalyzed intramolecular iodoamination of unfunctionalized olefins and subsequent ring opening of an aziridinium ion intermediate with alcohols/phenols. In the presence of a catalytic amount of MnI2 and 2 equiv of NaI, intramolecular aminoalkoxylation of different N-benzyl-5-methylhex-4-en-1-amine substrates proceeded readily in alcoholic solvents, leading to 2-(alkoxyalkyl)pyrrolidine products in up to 90% isolated yields.
P
However, aminoalkoxylation product 4a rather than haloamination product was obtained when substituted substrate 3a was subjected to the same reaction (Scheme 2, eq 1).
roline derivatives such as prolinols or prolinol ethers have been used as important chiral ligands/catalysts1 and chiral auxiliaries2 in a variety of asymmetric organic reactions. They also appear as subunits in bioactive natural products3 and pharmaceuticals.4 Traditionally, the preparation of prolinol derivatives can be realized from proline or 4-hydroxyproline through functional group transformation reactions. However, it is generally difficult to prepare structurally diversified pyrrolidine structures due to the limited structure variation of the starting materials.5 From the viewpoint of drug design and organic synthesis, it would be highly desirable to develop a general method for the preparation of prolinol structures. These have been realized via ring-opening of aziridinium ions6 and aminoalkoxylation of open-chain CC double bonds.7 In this paper, we report a general method for the preparation of prolinol ether type compounds as a continuation of our program on intramolecular aminocyclization of unfunctionalized olefins. Recently, we reported an MnI2-catalyzed iodocyclization of unfunctionalized CC double bonds. In the presence of a catalytic amount of MnI 2 and 4 equiv of NaI·2H2O, intramolecular cyclization of 4-penten-1-amine substrate 1a proceeded readily, leading to 5-exo-trig product which underwent isomerization to give the 6-endo-trig compound 2a as the final product (Scheme 1).8
Scheme 2. Aminoalkoxylation of Different Unfunctionalized Olefins
Substrate 5a bearing one substituent on the CC double bond gave a very complex mixture. Both syn- and anti-6a were isolated after careful separation of the mixture, plus some unidentifiable compounds (Scheme 2, eq 2). Further study showed that even terminal olefinic substrate 1a could be converted to aminoalkoxylation product 7a at elevated temperature (Scheme 2, eq 3). Given the potential application of prolinol ether type compounds in asymmetric organic reactions, we decided to study the reactions in detail. Reaction conditions were first optimized by carrying out the reactions with different amounts
Scheme 1. MnI2-Catalyzed Intramolecular Iodoamination of 1a
Received: January 26, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00284 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
substituents on the main chain generally gave products in low yields (entry 1 vs entries 10 and 11). Next, the preparation of ethyl prolinol ether-type compounds were carried out. The results are summarized in Table 2.
of MnI2, different reaction media, and different amounts of additives.9 Studies showed that no reaction was observed in the absence of MnI2. When 10 mol % of MnI2 was used as the catalyst, aminoethoxylation reactions could be realized in ethanol in the presence of 2 equiv of NaI, leading to product 4a in 91% yield. Aminoalkoxylations in other alcoholic solvents were not as successful as in ethanol. However, adding acetonitrile to the reaction mixture resulted in good conversion of the substrates (8a−11a) (Scheme 3). The use of sodium iodide was necessary to obtain a meaningful conversion, and both anhydrous sodium iodide and sodium iodide hydrate could be used as the additive.
Table 2. Preparation of Ethyl Prolinol Ethersa
Scheme 3. Aminoalkoxylation of 3a in Different Solvents
R1
R2
yieldb (%)
1 2 3 4 5 6 7c 8c 9d 10c 11c
8a 8b 8c 8d 8e 8f 8g 8h 8i 8j 8k
Ph Ph Ph Ph Ph Ph Ph Ph Ph −(CH2)5− Me
Bn 4-MeOBn 4-MeBn 4-(i-Pr)Bn 4-(O2N)Bn 4-FBn 4-BrBn 4-(MeO2C)Bn i-Pr Bn Bn
87 90 83 76 86 78 90 34 41 54 24
R1
R2
yieldb (%)
1 2 3 4 5 6 7 8c 9d 10c 11c 12
4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l
Ph Ph Ph Ph Ph Ph Ph Ph Ph −(CH2)5− Me Ph
Bn 4-MeOBn 4-MeBn 4-(i-Pr)Bn 4-(O2N)Bn 4-FBn 4-BrBn 4-(MeO2C)Bn i-Pr Bn Bn 4-NCBn
82 75 73 76 17 81 75 63 40 72 36 5
Comparing with the results of aminomethoxylations, the aminoethoxylation reactions were more sensitive to the structures of the substrates. While substrates with electrondonating groups in the 4-positions of the benzyl groups generally gave products in good isolated yields, substrates with electron-withdrawing groups at the 4-position gave products in low isolated yields. Again, the Thorpe−Ingold effect was observed in the reactions, and substrates 3j and 3k gave products in moderate and low isolated yields, respectively. Next, reactions in the presence of other alcoholic solvents were carried out to further extend the scope of the reaction. Reactions in the presence of n-PrOH, i-PrOH, i-BuOH, BnOH, and PhOH could all be realized, leading to the corresponding prolinol ether-type compounds in satisfactory isolated yields (Table 3). To further expand the application scope of this aminoalkoxylation reaction, terminal olefinic substrates were also subjected to the reactions. The results are listed in Scheme 4. When the reactions were carried out at elevated temperature, reactions in EtOH proceeded readily, giving 6-endo-trig aminoethoxylation products in satisfactory isolated yields (7a−d). At elevated temperature, the Thorpe−Ingold effect showed less impact on the reactions, and substrates with phenyl, cyclohexyl, or methyl groups could all be cyclized with similar yields (7a−c). When n-PrOH or i-BuOH was subjected to the reactions, similar substrate conversions were observed, but both 5-exo-trig (7e′ and 7f′) and 6-endo-trig (7e and 7f) products were obtained, possibly due to the slightly weaker nucleophilicity of n-PrOH and i-BuOH as well as the steric hindrance of the aziridinium ion intermediates. To confirm the skeleton of these compounds, an X-ray diffraction experiment on 12a was carried out, and the ORTEP drawing of 12a showed a typical prolinol ether type structure.
Table 1. Preparation of Different Prolinol Methyl Ethersa
product
product
a All reactions were carried out with 0.25 mmol of 3, 0.025 mmol of MnI2 (10 mol %), and 0.5 mmol of NaI (2 equiv) in EtOH (1 mL) at 35 °C for 48 h. bIsolated yield. cNaI (0.75 mmol, 3 equiv) was added to the reaction mixture. d100 mol % of MnI2 was used.
After a general method for the preparation of prolinol ethertype compounds was established, reactions with different alcohols were tested in an attempt to prepare structurediversified prolinol ethers. Reactions in MeOH−MeCN were first carried out. The results are summarized in Table 1.
entry
entry
a All reactions were carried out with 0.25 mmol of 3, 0.025 mmol of MnI2 (10 mol %), and 0.5 mmol of NaI (2 equiv) in MeOH/MeCN (1:3) (1 mL) at 35 °C for 48 h. bIsolated yield. c45 °C. d100 mol % of MnI2.
As shown in Table 1, most reactions proceeded readily, leading to intramolecular aminoalkoxylation products in up to 90% isolated yields. Electronic properties of the substituents on the benzene rings generally showed less effect on the reactions (Table 1, entries 1−7), except for substrate 3h (entry 8), which bore a carboxylate functional group at the 4-position of the benzyl group. The low reactivity of this substrate might be due to the coordination of the carbonyl group to MnI2 which diminished the catalytic activity of the latter. A Thorpe−Ingold effect was observed in the reactions, and substrates with small B
DOI: 10.1021/acs.orglett.7b00284 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
reaction system, the prolinol ether type product could be formed either via direct etherification of the resulting iodoamination product or via regioselective nucleophilic ring opening of an aziridinium ion intermediate.13 Results from control experiments indicated that no aminoalkoxylation product could be obtained when compound 14 was allowed to react in ethanol at 35 °C for 48 h (Scheme 5), thus ruling out the possibility of a direct etherification pathway.
Table 3. Preparation of Prolinol Ether Compounds Bearing Different Alkoxyl Groupsa,b
entry
product
R1
R2
R3
yieldb (%)
1 2 3 4 5 6 7c 8 9c 10c 11 12 13 14 15 16c 17c 18 19c 20c 21 22
9a 9b 9c 9d 9f 9g 9h 9i 9j 9k 10a 11a 11c 11d 11f 11g 11h 11i 11j 11k 12a 13a
Ph Ph Ph Ph Ph Ph Ph Ph −(CH2)5− Me Ph Ph Ph Ph Ph Ph Ph Ph −(CH2)5− Me Ph Ph
Bn 4-MeOBn 4-MeBn 4-(i-Pr)Bn 4-FBn 4-BrBn 4-(MeO2C)Bn i-Pr Bn Bn Bn Bn 4-MeBn 4-(i-Pr)Ph 4-FBn 4-BrBn 4-(MeO2C)Bn i-Pr Bn Bn Bn Bn
n-Pr n-Pr n-Pr n-Pr n-Pr n-Pr n-Pr n-Pr n-Pr n-Pr i-Pr i-Bu i-Bu i-Bu i-Bu i-Bu i-Bu i-Bu i-Bu i-Bu Bn Ph
72 65 80 44 26 86 85 31 73 71 45 73 71 65 79 80 75 30 75 70 65 38
Scheme 5. Control Experiment of 14
DFT calculations were also carried out to study the effect of substituents on the reactivity of the aziridinium ion intermediates.9 Three different aziridinium ion intermediates A−C were calculated (Figure 1). Calculation results indicated
Figure 1. Aziridinium ion intermediates with different substituents.
that substituents had significant effects on the structures and activities of the aziridinium ion intermediates A−C.9 For intermediate A, C5 was more susceptible to nucleophilic attack, and compound 7a would be obtained as the final product. For intermediate C, C6 was more susceptible to nucleophilic attack, and compound 4a would be obtained as the final product. From intermediate B, nucleophilic attack on C6 was preferred, and both syn- and anti- 5-exo-trig products could be formed. On the basis of the literature results and our understanding of MnI2-catalyzed iodocyclization reactions, a possible reaction pathway is proposed as shown in Scheme 6. The first step is the
a All reactions were carried out with 0.25 mmol of 3, 0.025 mmol of MnI2 (10 mol %), and 0.5 mmol of NaI (2 equiv) in R3OH/MeCN (1:3) (1 mL) at 35 °C for 48 h. bIsolated yield. cNaI (0.75 mmol, 3 equiv) was added to the reaction mixture, and the solvent was R3OH.
Scheme 4. MnI2-Catalyzed Aminoalkoxylation of Different N-Benzyl-4-penten-1-amine Substratesa,b
Scheme 6. Possible Pathways for the Formation of Prolinol Ether Products
a
All reactions were carried out with 0.5 mmol of N-benzyl substrates, 1 mmol of NaI (2 equiv), and 0.1 mmol of MnI2 (20 mol %) in R3OH (3 mL) at 80 °C for 24 h. bIsolated yield.
MnI2-catalyzed iodoamination of the substrate, providing the corresponding 2-(2-iodo-2-propyl)-4,4-diphenylpyrrolidine,8 which is converted to aminoalkoxylation product via ringopening of the aziridinium ion intermediate. In the case of compound 14, the nucleophilicity of the nitrogen atom is reduced, and the formation of the aziridinium ion intermediate is difficult due to the electron-withdrawing property of the tosyl group.Therefore, the compound could not be converted to the corresponding prolinol ether product.
Further, reaction of 3a in EtOH on gram scale was also carried out, and product 4a was produced in 87% isolated yield.9 De Kimpe et al. developed the electrophile-induced cyclization of γ,δ-alkenylimines10 and detailed the skeletal rearrangement of 1-pyrrolidinium salts with alkoxides to afford 2,5-dialkyoxylated piperidines.11 DFT calculations were also carried out to study the possible pathways of the halide-induced ring-opening reactions of aziridinium ions.12 In the current C
DOI: 10.1021/acs.orglett.7b00284 Org. Lett. XXXX, XXX, XXX−XXX
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Ruggeri, P.; Fumagalli, L.; Binda, M.; Mucchietto, V.; Sciaccaluga, M.; Budriesi, R.; Fucile, S.; Pallavicini, M. J. Med. Chem. 2015, 58, 6665. (e) Bharate, S. B.; Singh, B.; Kachler, S.; Oliveira, A.; Kumar, V.; Bharate, S. S.; Vishwakarma, R. A.; Klotz, K. N.; Gutiérrez de Teran, H. G. J. Med. Chem. 2016, 59, 5922. (5) Mazzini, C.; Sambri, L.; Regeling, H.; Zwanenburg, B.; Chittenden, G. J. F. J. Chem. Soc., Perkin Trans. 1 1997, 3351. (6) Dolfen, J.; Yadav, N. N.; De Kimpe, N.; D’Hooghe, M.; Ha, H.-J. Adv. Synth. Catal. 2016, 358, 3485. (7) (a) Jahn, U.; Aussieker, S. Org. Lett. 1999, 1, 849. (b) Xu, H.-C.; Moeller, K. D. J. Am. Chem. Soc. 2008, 130, 13542. (c) Li, H.; Widenhoefer, R. A. Tetrahedron 2010, 66, 4827. (d) Liskin, D. V.; Sibbald, P. A.; Rosewall, C. F.; Michael, F. E. J. Org. Chem. 2010, 75, 6294. (e) Zhou, L.; Tan, C. K.; Zhou, J.; Yeung, Y. Y. J. Am. Chem. Soc. 2010, 132, 10245. (f) Xu, H.-C.; Moeller, K. D. J. Am. Chem. Soc. 2010, 132, 2839. (g) Nakanishi, M.; Minard, C.; Retailleau, P.; Cariou, K.; Dodd, R. H. Org. Lett. 2011, 13, 5792. (h) Herrera-Leyton, C.; Madrid-Rojas, M.; Lopez, J. J.; Canete, A.; Hermosilla-Ibanez, P.; Perez, E. G. ChemCatChem 2016, 8, 2015. (8) Sun, H.; Cui, B.; Liu, G.-Q.; Li, Y.-M. Tetrahedron 2016, 72, 7170. (9) See the Supporting Information for details. (10) (a) De Kimpe, N.; Boelens, M.; Piqueur, J.; Baele, J. Tetrahedron Lett. 1994, 35, 1925. (b) De Kimpe, N.; Boelens, M. J. Chem. Soc., Chem. Commun. 1993, 916. (11) De Kimpe, N.; Boelens, M.; Contreras, J. Tetrahedron Lett. 1996, 37, 3171. (12) D’Hooghe, M.; Catak, S.; Stanković, S.; Waroquier, M.; Kim, Y.; Ha, H.-J.; Van Speybroeck, V.; De Kimpe, N. Eur. J. Org. Chem. 2010, 2010, 4920. (13) Anxionnat, B.; Robert, B.; George, P.; Ricci, G.; Perrin, M.-A.; Gomez Pardo, D.; Cossy, J. J. Org. Chem. 2012, 77, 6087.
In summary, prolinol ether type compounds could be prepared starting from unfunctionalized olefins. Preliminary control experiments and DFT calculations indicated that the reaction proceeded via an intramolecular iodoamination− aziridinium ion ring-opening sequence. Under the optimized conditions, aminoalkoxylation of unfunctionalized olefins could be realized in the presence of a variety of alcohols such as MeOH, EtOH, n-PrOH, i-PrOH, i-BuOH, PhOH, or BnOH, giving the corresponding prolinol ether-type compounds with satisfactory yields. The structures of the products were confirmed by NMR, HRMS, as well as X-ray diffraction experiments.
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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.7b00284. DFT calculation results, characterization data for the products, and X-ray diffraction data of compound 12a (PDF) Crystallographic data for 12a (CIF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Yue-Ming Li: 0000-0003-2632-9253 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We acknowledge financial support from the National Natural Science Foundation of China (NSFC 21672106, NSFC 21272121).
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REFERENCES
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DOI: 10.1021/acs.orglett.7b00284 Org. Lett. XXXX, XXX, XXX−XXX
