Facile Construction of Tetrahydropyrrolizines by Iron-Catalyzed

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

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Facile Construction of Tetrahydropyrrolizines by Iron-Catalyzed Double Cyclization of Alkene-Tethered Oxime Esters with 1,2Disubstituted Alkenes Takuya Shimbayashi, Daiki Nakamoto, Kazuhiro Okamoto,* and Kouichi Ohe* Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan S Supporting Information *

ABSTRACT: The iron-catalyzed cycloaddition reaction of alkene-tethered oxime esters with 1,2-disubstituted alkenes afforded tetrahydropyrrolizines, the structural motif often seen in bicyclic alkaloids. The reaction proceeds through consecutive cycloaddition reactions. These include, first, intramolecular cyclization, followed by intermolecular cyclization with a 1,2-disubstituted alkene in a regioselective manner where an imine moiety first generated plays a pivotal role.

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triggered intensive studies on the development of synthetically useful reactions.4−6 The regioselectivity of a radical addition to an alkene is greatly affected by the stability of the formed radical intermediate. Hence, α-selective radical addition to β-functionalized Michael acceptors is typically difficult (Scheme 1, eq 2). Such a reaction, in which cyclic β-aryl Michael acceptors are used in a photoredox catalytic system, has been reported; however, the selectivity was not so high when an acyclic acceptor was used.7 We recently investigated the N−O bond cleaving transformation of oxime derivatives using various late transition metal complexes.8 During the course of our previous study on iron-catalyzed aminative cyclization/intermolecular arylation reactions using simple arenes (Scheme 1, eq 1),8h in which the interaction of alkyl radical species with the iron catalyst was of great interest, we envisioned that the reaction of oxime esters bearing an alkene moiety with activated alkenes could also be catalyzed by iron. Herein, we report the α-selective radical addition to 1,2disubstituted alkenes having an electron-withdrawing group, leading to a second cyclization, which enables a straightforward single-step synthesis of tetrahydropyrrolizines (Scheme 1, eq 3). The products are chemically and biologically important pyrrolizidine alkaloids, occurring in abundance in natural products and having prominent biological activities.9 The reaction of oxime ester 1a with β-phenyl enone was carried out under reaction conditions similar to those we reported previously for an arylation reaction.8h We were delighted to find that the reaction of 1a with enone 2a in the presence of 10 mol % of Fe(OTf)2 and bipyridyl ligand L1 in benzene at 120 °C afforded tetrahydropyrrolizine 3aa (major

minyl radicals are very valuable intermediates in the synthesis of N-heterocyclic compounds. They can be generated by homolysis of N−X bonds in imines bearing a leaving group (X) on their nitrogen atoms.1 Zard demonstrated the synthetic utility of iminyl radicals in his seminal work on intramolecular radical cyclization using γ,δ-unsaturated Nsulphenylimine or Barton’s ester of O-carboxymethyl oxime ether, in which the resulting carbon-centered radical adds to an activated alkene, such as an acrylate ester, at its β-position (Scheme 1, eq 1).2 Later, Narasaka reported a transition-metalcatalyzed or single-electron-transfer-induced N−O bond cleaving transformation of oxime ethers or esters,3 which Scheme 1. Radical Cascade Leading to N-Heterocycles Involving Iminyl Radicals

Received: April 5, 2018

© XXXX American Chemical Society

A

DOI: 10.1021/acs.orglett.8b01073 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters diastereomer shown) in 63% yield and with a 6:1 diastereomer ratio without the formation of arylated product 4a (Scheme 2). Scheme 2. Initial Attempt

Figure 1. X-ray structure of 3aa. Major diastereomer (left) and minor diastereomer (right).

We then optimized the reaction conditions, including the catalyst and reaction temperature (Table 1). At 80 °C, a slightly Table 1. Optimization of Reaction Conditions

entry

[Fe] (mol %)

ligand (mol %)

1 2 3 4 5 6 7 8b 9b

Fe(OTf)2 (10) Fe(OTf)2 (10) Fe(OTf)3 (10) Fe(OAc)2 (10) FeCl2 (10) FeF2 (10) FeF2 (10) FeF2 (5) FeSO4·7H2O (5)

L1 (10) L1 (10) L1 (10) L1 (10) L1 (10) L1 (10) dtbpy (10) dtbpy (5) dtbpy (5)

Table 2. Reaction with Various Alkenesa

a

temp (°C)

3aa (%)

dr

120 80 120 120 120 120 120 120 120

63 58 42 56 55 75 77 81 (75)c 82 (76)c

6.3:1 6.1:1 6.5:1 6.0:1 6.5:1 6.2:1 6.0:1 6.0:1 6.0:1

entry

2

R

EWG

yield (%)b

dr

1 2 3d 4d 5 6d 7d 8e 9e 10e 11e 12e 13e 14e 15e 16e

2a 2b 2c 2d 2e 2f 2g 2h 2i 2j 2k 2l 2m 2n 2o 2p

Ph 4-CNC6H4 4-BrC6H4 4-MeOC6H4 4-Me2NC6H4 2-pyridyl 2-naphthyl Ph Ph Ph Ph Ph Ph Ph Me MeOCO

MeCO MeCO MeCO MeCO MeCO MeCO MeCO iPrCO t-BuCO PhCO EtOCO Me2NCO HCO NC PhCO MeOCO

76 76 75 60 55 60 64 57 35 52 60 44 47 61 13 59

6.0:1 −c 7.6:1 9.0:1 6.2:1 −c −c 7.1:1 −c −c −c −c 8.4:1 10:1 −c −c

a Reaction conditions: 1a (0.20 mmol), 2a (0.30 mmol), [Fe] (0.020 or 0.010 mmol), ligand (0.020 or 0.010 mmol), and C6H6 (1.5 mL). dr = diastereomer ratio. Yields and dr were determined by 1H NMR using 1,4-dioxane as an internal standard. b3.0 equiv of 2a. cIsolated yield.

NMR yield (%) [dr] 82 84 84 74 66 64 73 65 43 62 79 66 50 68 34 69

[6.0:1] [9.5:1] [7.4:1] [5.7:1] [3.4:1] [15:1] [7:1] [6.3:1] [5.1:1] [5.0:1] [6.2:1] [3.4:1] [6.1:1] [7.5:1] [10:1] [5.9:1]

Reaction conditions: 1a (0.6 mmol), 2 (1.2 mmol), FeSO4·7H2O (0.03 mmol, 5 mol %), dtbpy (0.03 mmol, 5 mol %), and C6H6 (4.5 mL). dr = diastereomer ratio. EWG = electron-withdrawing group. b Isolated yield. cOnly one major diastereomer was obtained. d10 mol % of FeSO4·7H2O and dtbpy were used. e1a (0.4 mmol), 2 (1.2 mmol), FeSO4·7H2O (0.02 mmol, 5 mol %), dtbpy (0.02 mmol, 5 mol %), and C6H6 (3.0 mL) were used. a

lower yield of 3aa was obtained (Table 1, entry 2). Use of FeF2 resulted in a significant increase in product yield (Table 1, entries 3−6). After ligand screening, 4,4′-di-tert-butyl-2,2′bipyridyl (dtbpy) was determined to be the best ligand (Table 1, entry 7). Reducing the catalyst loading to 5 mol % and, simultaneously, increasing the amount of 2a afforded the desired product 3aa in 75% isolated yield (Table 1, entry 8). Later, it was found that FeSO4·7H2O, which is a cheaper iron source and easier to handle, gave the same results as those obtained with FeF2 (Table 1, entry 9). The structures of 3aa and the minor diastereomer were unambiguously determined by X-ray crystallographic analysis (Figure 1). DFT analyses of the optimized structure of both diastereomers indicated that the major one is more stable than the minor one (2.4 kcal/mol difference). The optimized reaction conditions were then applied to reactions with various 1,2-disubstituted alkenes (Table 2). The reaction of 1a with alkenes having both electron-withdrawing and -donating substituents on the aryl group at the β-position (2b−2e) afforded the corresponding product 3 in good yields (Table 2, entries 2−5). Electron-deficient arenes 2b and 2c gave better results. 2-Pyridyl- or 2-naphthyl-substituted alkenes

2f and 2g were also suitable (Table 2, entries 6 and 7). Isolated yields of minor diastereomers were lower in some cases due to their instability during purification; hence, the diastereomer ratio was generally higher than that of a crude mixture. Ketones having iPr (2h), t-Bu (2i), and Ph (2j) groups were also applicable to the cycloaddition reaction; they afforded the corresponding adducts in fair to good yields (Table 2, entries 8−10). Not only ketones but also ester 2k, amide 2l, aldehyde 2m, and nitrile 2n could be effective reaction partners, affording the corresponding tetrahydropyrrolizines in good yields (Table 2, entries 11−14). The reaction with trans-1-phenyl-1-buten-1one 2o afforded the corresponding cycloadduct in modest yield (Table 2, entry 15). The reaction system could be applied to maleate or fumarate 2p, to afford the desired cycloadduct 3ap in good yield (Table 2, entry 16).10 The reaction could also be scaled up to 5.5 mmol of 1a and 2.0 equiv of 2a, to afford 1.082 g of 3aa (major diastereomer) together with 178.5 mg of a minor diastereomer (Scheme 3). B

DOI: 10.1021/acs.orglett.8b01073 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

H atom at the C-5 position of tetrahydropyrrolizine, D2O was added to the standard reaction. 1H NMR analysis of products showed the formation of deuterated product 3aa-d-major (91% D was incorporated) and 3aa-d-minor (87% D was incorporated) (eq 5). This indicated that the source of the H

Scheme 3. Gram Scale Experiment

Next, the scope of oxime esters was examined (Scheme 4). Oxime ester 1b bearing a methyl group at the R1 position gave Scheme 4. Scope of Oxime Estersa atom at the C-5 position is mainly an external proton, i.e., from water in a catalyst precursor or solvent; it is not from an intramolecular H atom transfer. Thus, protonation at the C-5 position with D2O is more likely to occur. A plausible mechanism, based on the above-mentioned experiments, is shown in Scheme 5.13 Taking the findings of Scheme 5. Plausible Mechanism

a

Reaction conditions: 1 (0.4 or 0.6 mmol), 2a (1.2 or 1.8 mmol, 3.0 equiv), FeSO4·7H2O (0.02 or 0.03 mmol, 5 mol %), dtbpy (0.02 or 0.03 mmol, 5 mol %), and C6H6 (3.0 or 4.5 mL). Isolated yields are shown. Diastereomer ratios are shown in brackets. major = only major isomer could be isolated. bDetermined by 1H NMR.

the sterically demanding product 3ba with modest diastereoselectivity. Oxime ester 1c bearing a methyl group at the R2 position gave a mixture of three diastereomers of 3ca. The reaction of oxime esters 1d without substituents at the R3 and R4 positions also proceeded smoothly to give pyrrolizine 3da in moderate yield and with good diastereoselectivity. Spirocyclic product 3ea was also obtained in good yield. The other aryl groups, such as 2-pyridyl and 2-naphthyl at the R5 position (1f and 1g), were tolerated in the reaction system.11 Some experiments showed mechanistic implications.12 Addition of TEMPO as a radical scavenger to the reaction mixture under the standard conditions resulted in complete inhibition of the cycloaddition reaction. The reaction afforded the TEMPO adduct in 17% yield (eq 4). This result implies

our previous work into consideration,8h the N−O bond of 1a is cleaved by iron to form intermediate A, which undergoes 5-exo cyclization to give B. Intermediate B may be in equilibrium with the corresponding iron adduct C. Regioselective radical addition with alkene 2a then occurs to give D. DFT analyses show that α-addition is lower in energy than β-addition, by 1.3 kcal/mol in the transition state.14 D undergoes single-electron oxidation by iron to form cation E, followed by ionic cyclization

involvement of the radical intermediate formed by intramolecular cyclization of 1a, initiated by the N−O bond cleavage by iron. To obtain some insight into the source of the C

DOI: 10.1021/acs.orglett.8b01073 Org. Lett. XXXX, XXX, XXX−XXX

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to give bicyclic iminium G. On the other hand, radical cyclization with an imine moiety15 to give F prior to oxidation leading to G is also a possible reaction pathway. This is supported by the reaction with electron-deficient alkenes such as 2b, 2c, and 2p. Both pathways compete in the catalytic system. The following deprotonation by pivalate occurs to give azomethine ylide intermediate H, which can have a canonical resonance structure H′.16 Finally, to complete the reaction, protonation at the C-5 anion followed by deprotonation at the α-position to an acyl group gives 3aa.17,18 To demonstrate the synthetic utility of tetrahydropyrrolizines obtained by this one-step cyclization, derivatization of 3aa was attempted. Tetrahydropyrrolizine 3aa was readily oxidized by DDQ to afford dihydropyrrolizine 6aa and 7aa, quantitatively (Scheme 6a). Furthermore, reduction of 3aa with NaBH3CN

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Kazuhiro Okamoto: 0000-0001-8562-3167 Kouichi Ohe: 0000-0001-8893-8893 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This study has been financially supported by a Grant-in-aid for JSPS Research Fellow (T.S.) (Grant No. 17J09627), Kansai Research Foundation for technology promotion (K.O.), and JSPS KAKENHI (a Scientific Research (C); Grant No. 17K05861).

Scheme 6. Derivatization of Tetrahydropyrrolizine 3aa

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REFERENCES

(1) For reviews, see: (a) Zard, S. Z. Synlett 1996, 1996, 1148. (b) Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543. (c) Zard, S. Z. Chem. Soc. Rev. 2008, 37, 1603. (d) Jackman, M. M.; Cai, Y.; Castle, S. L. Synthesis 2017, 49, 1785. (2) (a) Boivin, J.; Fouquet, E.; Zard, S. Z. Tetrahedron Lett. 1990, 31, 3545. (b) Boivin, J.; Fouquet, E.; Zard, S. Z. Tetrahedron Lett. 1991, 32, 4299. (c) Boivin, J.; Fouquet, E.; Zard, S. Z. Tetrahedron 1994, 50, 1745. (d) Boivin, J.; Fouquet, E.; Schiano, A.-M.; Zard, S. Z. Tetrahedron 1994, 50, 1769. (3) (a) Uchiyama, K.; Hayashi, Y.; Narasaka, K. Chem. Lett. 1998, 27, 1261. (b) Uchiyama, K.; Hayashi, Y.; Narasaka, K. Tetrahedron 1999, 55, 8915. (c) Koganemaru, Y.; Kitamura, M.; Narasaka, K. Chem. Lett. 2002, 31, 784. (4) For reviews, see: (a) Narasaka, K.; Kitamura, M. Eur. J. Org. Chem. 2005, 2005, 4505. (b) Kitamura, M.; Narasaka, K. Bull. Chem. Soc. Jpn. 2008, 81, 539. (c) Huang, H.; Ji, X.; Wu, W.; Jiang, H. Chem. Soc. Rev. 2015, 44, 1155. (d) Race, N. J.; Hazelden, I. R.; Faulkner, A.; Bower, J. F. Chem. Sci. 2017, 8, 5248. (5) For selected examples, see: (a) Nishimura, T.; Yoshinaka, T.; Nishiguchi, Y.; Maeda, Y.; Uemura, S. Org. Lett. 2005, 7, 2425. (b) Liu, S.; Yu, Y.; Liebeskind, L. S. Org. Lett. 2007, 9, 1947. (c) Ren, Z.-H.; Zhang, Z.-Y.; Yang, B.-Q.; Wang, Y.-Y.; Guan, Z.-H. Org. Lett. 2011, 13, 5394. (d) Bingham, M.; Moutrille, C.; Zard, S. Z. Heterocycles 2014, 88, 953. (e) Faulkner, A.; Race, N. J.; Scott, J. S.; Bower, J. F. Chem. Sci. 2014, 5, 2416. (f) Du, W.; Zhao, M.-N.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H. Chem. Commun. 2014, 50, 7437. (g) Faulkner, A.; Scott, J. S.; Bower, J. F. J. Am. Chem. Soc. 2015, 137, 7224. (h) Race, N. J.; Faulkner, A.; Shaw, M. H.; Bower, J. F. Chem. Sci. 2016, 7, 1508. (i) Zhao, M.-N.; Ren, Z.-H.; Yu, L.; Wang, Y.-Y.; Guan, Z.-H. Org. Lett. 2016, 18, 1194. (j) Bao, X.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2017, 56, 9577. (k) Zhu, Z.; Tang, X.; Li, J.; Li, X.; Wu, W.; Deng, G.; Jiang, H. Org. Lett. 2017, 19, 1370. (l) Yang, H.-B.; Selander, N. Chem. - Eur. J. 2017, 23, 1779. (m) Yang, H.-B.; Pathipati, S. R.; Selander, N. ACS Catal. 2017, 7, 8441. (6) More recently, the use of photoredox catalysis has also been reported; see: (a) Davies, J.; Booth, S. G.; Essafi, S.; Dryfe, R. A. W.; Leonori, D. Angew. Chem., Int. Ed. 2015, 54, 14017. (b) Cai, S.-H.; Xie, J.-H.; Song, S.; Ye, L.; Feng, C.; Loh, T.-P. ACS Catal. 2016, 6, 5571. (c) Jiang, H.; Studer, A. Angew. Chem., Int. Ed. 2017, 56, 12273. (d) Davies, J.; Sheikh, N. S.; Leonori, D. Angew. Chem., Int. Ed. 2017, 56, 13361. (7) Lovett, G. H.; Sparling, B. A. Org. Lett. 2016, 18, 3494. (8) (a) Okamoto, K.; Oda, T.; Kohigashi, S.; Ohe, K. Angew. Chem., Int. Ed. 2011, 50, 11470. (b) Okamoto, K.; Shimbayashi, T.; Tamura, E.; Ohe, K. Chem. - Eur. J. 2014, 20, 1490. (c) Shimbayashi, T.; Okamoto, K.; Ohe, K. Synlett 2014, 25, 1916. (d) Okamoto, K.; Shimbayashi, T.; Yoshida, M.; Nanya, A.; Ohe, K. Angew. Chem., Int.

under acid conditions afforded pyrrolizidine 8aa and its diastereomer 8aa′ in good yield (Scheme 6b).19 After treating the reaction mixture with NaOH after reduction, the major diastereomer 8aa was obtained exclusively. These results indicate that tetrahydropyrrolizines could provide a platform for various pyrrolizidine alkaloids.9 In summary, we have demonstrated the iron-catalyzed cyclization of alkene-tethered oxime esters with activated alkenes to afford tetrahydropyrrolizines in good yields. The imine moiety undergoes unprecedented formal radical addition to afford a bicyclic skeleton within a single operation. This system enables the straightforward single-step synthesis of pyrrolizidine derivatives, which may be of benefit to future pharmacological studies. Studies on enantioselective access to these pyrrolizidines is ongoing.

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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.8b01073. Expeprimental procedures, additional experimental data, and compounds characterizeation data (PDF) Accession Codes

CCDC 1834309−1834312 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. D

DOI: 10.1021/acs.orglett.8b01073 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Ed. 2016, 55, 7199. (e) Okamoto, K.; Sasakura, K.; Shimbayashi, T.; Ohe, K. Chem. Lett. 2016, 45, 988. (f) Shimbayashi, T.; Okamoto, K.; Ohe, K. Chem. - Eur. J. 2017, 23, 16892. (g) Okamoto, K.; Nanya, A.; Eguchi, A.; Ohe, K. Angew. Chem., Int. Ed. 2018, 57, 1039. (h) Shimbayashi, T.; Okamoto, K.; Ohe, K. Chem. - Asian J. 2018, 13, 395. (9) For recent reviews on pyrrolizidine alkaloids, see: (a) Robertson, J.; Stevens, K. Nat. Prod. Rep. 2014, 31, 1721. (b) Robertson, J.; Stevens, K. Nat. Prod. Rep. 2017, 34, 62. (10) Irrespective of the stereochemistry of 2p, 3ap was obtained in almost identical yield with similar diastereoselectivity. (11) When alkyl ketoxime (R5 = alkyl) was used, the desired product was hardly obtained due to the formation of a complex mixture. (12) See Supporting Information for more detailed mechanistic studies. (13) In the catalytic cycle, there may be an equilibrium between free radical species and corresponding iron adducts. Such equilibrium is proposed to be involved in the iron-catalyzed cross-coupling or borylation of aryl chloride. See: (a) Hatakeyama, T.; Hashimoto, T.; Kathriarachchi, K. K. A. D. S.; Zenmyo, T.; Seike, H.; Nakamura, M. Angew. Chem., Int. Ed. 2012, 51, 8834. (b) Adak, L.; Kawamura, S.; Toma, G.; Takenaka, T.; Isozaki, K.; Takaya, H.; Orita, A.; Li, H. C.; Shing, T. K. M.; Nakamura, M. J. Am. Chem. Soc. 2017, 139, 10693. (c) Yoshida, T.; Ilies, L.; Nakamura, E. ACS Catal. 2017, 7, 3199. (14) The energy difference between two transition states is not large enough for complete selectivity. There may be a more attractive interaction of the iron center with an electron-withdrawing group in a transition state. (15) For radical addition to a N atom of the CN bond, see: (a) Bowman, W. R.; Stephenson, P. T.; Terrett, N. K.; Young, A. R. Tetrahedron 1995, 51, 7959. (b) Ryu, I.; Matsu, K.; Minakata, S.; Komatsu, M. J. Am. Chem. Soc. 1998, 120, 5838. (c) Johnston, J. N.; Plotkin, M. A.; Viswanathan, R.; Prabhakaran, E. N. Org. Lett. 2001, 3, 1009 and references therein. (16) (a) Pahadi, N. K.; Paley, M.; Jana, R.; Waetzig, S. R.; Tunge, J. A. J. Am. Chem. Soc. 2009, 131, 16626. (b) Deb, I.; Das, D.; Seidel, D. Org. Lett. 2011, 13, 812 and references therein. (17) Diastereoselectivity is determined by protonation on C-5. It was confirmed that the minor diastereomer was converted to the major one under the catalytic conditions. The selectivity will be influenced by the difference in energy between two isomers (2.4 kcal/mol) and the reversible protonation/deprotonation pathway leading to azomethine ylide intermediates G and H. See Supporting Information. (18) The reaction of 2a-d having a deuterium at the β-position afforded 3aa-d (major and minor) including about 30% deuterium at the C-5 position. This result supports the fact that deprotonation of the intermediate F at the C-3 position takes place prior to the formation of H. See Supporting Information. (19) For the diastereoselectivity, see Supporting Information.

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DOI: 10.1021/acs.orglett.8b01073 Org. Lett. XXXX, XXX, XXX−XXX