Three-Component Reactions of Diazoesters, Aldehydes, and Imines

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Three-Component Reactions of Diazoesters, Aldehydes, and Imines Using a Dual Catalytic System Consisting of a Rhodium(II) Complex and a Lewis Acid Yasunori Toda, Wakatake Kaku, Makoto Tsuruoka, Sho Shinogaki, Tomoka Abe, Hideaki Kamiya, Ayaka Kikuchi, Kennosuke Itoh,† and Hiroyuki Suga* Department of Materials Chemistry, Faculty of Engineering, Shinshu University, 4-17-1 Wakasato, Nagano 380-8553, Japan S Supporting Information *

ABSTRACT: A dual catalytic system, dirhodium tetrapivalate/ytterbium(III) triflate, enables the three-component reactions of α-alkyl-α-diazoesters, aromatic aldehydes, and Nbenzylidenebenzylamine derivatives to afford the corresponding β-amino alcohols in good yields after hydrolysis of the oxazolidine cycloadducts, whereas no β-amino alcohols are obtained in the absence of ytterbium(III) triflate. A similar dual catalytic system, dirhodium tetraacetate/ytterbium(III) triflate, is found to be effective in accelerating the reactions of α-aryl-αdiazoesters in high yields. Furthermore, the reactions using dimethyl diazomalonate are described.

benzaldehyde, and N-benzylidenebenzylamine was demonstrated to afford the oxazolidine cycloadduct via the rhodium(II)-catalyzed carbonyl ylide formation (Scheme 2a).7a,b High to good yields and high stereoselectivities were achieved with the use of AgSbF6 in the three-component reaction of ethyl diazoacetate, p-bromobenzaldehyde, and Nbenzylideneaniline derivatives, whereas the cycloaddition did not proceed in the absence of the silver salt (Scheme 2b).7c In contrast, the reactions of α-aryl-substituted α-diazoesters have been limited to the use of electron-deficient imines such as pnitro- or p-cyanobenzaldehyde-derived N-tosyl imines (Scheme 2c).8 In these reports, it has been found that the reaction of methyl phenyldiazoacetate, benzaldehyde, and Nbenzylidenebenzylamine resulted in dominant epoxide formation from the corresponding carbonyl ylide.7b,8 Notably, the reaction scope of α-alkyl-substituted α-diazoesters has not been demonstrated, probably due to competing β-hydrogen elimination from the corresponding carbenoids and the low reactivity of imines as dipolarophiles. In this paper, we demonstrate that three-component reactions of α-alkyl-αdiazoesters, benzaldehyde, and N-benzylidenebenzylamines proceed using a dual catalytic system consisting of a rhodium(II) complex and Yb(OTf)3 to give 1,2-amino alcohols after hydrolysis of the corresponding carbonyl ylide cycloadducts. In addition, for both α-alkyl-α-diazoesters and α-aryl-α-diazoesters, as well as dimethyl diazomalonate, the scope of imines in the three-component reactions has been investigated to expand the three-component system.

1,3-Dipolar cycloadditions between carbonyl ylides and dipolarophiles are one of the most straightforward protocols for the synthesis of 5-membered oxa-heterocycles.1,2 Intramolecular carbenoid-carbonyl cyclization reactions are wellknown as efficient methods for the generation of carbonyl ylides, and they are applicable to a wide range of dipolarophiles. These sequences have been widely utilized for stereoselective syntheses of a variety of oxygen-functionalized polycyclic compounds.2 In contrast to cycloadditions involving an intramolecular ylide formation, the extension to intermolecular carbenoid-carbonyl reactions has been limited to highly reactive dipolarophiles, such as electron-deficient alkenes and alkynes, because of competitive cycloadditions with the carbonyl compounds as dipolarophiles (see Scheme 1).1g,3,4 Two electronically different types of carbonyl Scheme 1. Carbonyl Ylide Cycloadditions Involving Intermolecular Ylide Formation

compounds could be used for the selective formation of one type of the carbonyl ylide as the 1,3-dipole, which then reacts with the other carbonyl compound in some cases.5 Among dipolarophiles used in carbonyl ylide cycloadditions, there are few examples of reactions using imines as the dipolarophiles,6 wherein ethyl diazoacetate,7 α-aryl-α-diazoesters,8 and dimethyl diazomalonate9 have been employed with aldehydes to generate the carbonyl ylides. For example, the first three-component reaction of ethyl diazoacetate, © XXXX American Chemical Society

Received: March 16, 2018

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DOI: 10.1021/acs.orglett.8b00865 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

Table 1. Three-Component Reactions of α-Diazoester (1a), Benzaldehyde (2), and Imine (3)a

Scheme 2. Rh-Catalyzed Three-Component Reactions of Diazoesters, Aldehydes, and Imines

Initially, the three-component reactions of ethyl 2diazohydrocinnamate (1a) (1.5 equiv), benzaldehyde (2a) (1.5 equiv), and N-benzylidenebenzylamine (3a) were carried out in the presence of a rhodium(II) complex (2 mol %) and Yb(OTf)3 (20 mol %) (see Table 1). The reactions were generally performed by adding a CH2Cl2 solution of 1a dropwise to the mixture of 2a and 3a in CH2Cl2. The products were isolated as the corresponding amino alcohols 5a after hydrolysis of 4a in the three-component reaction mixture by treatment with p-toluenesulfonic acid (PTSA) in EtOH/H2O (95:5). The conditions at 25 °C using dirhodium tetraacetate (Rh2(OAc)4) or dirhodium tetrapivalate (Rh2Piv4) as the rhodium(II) catalyst with the addition of 1a over a period of 1.5 or 12 h resulted in low to moderate yields of anti- and syn-5a (33%−57%) with 50:50−62:38 diastereomeric ratios (entries 1−4 in Table 1). Under these conditions, a considerable amount of (Z)-ethyl cinnamate, which is the βelimination product from the rhodium carbenoid, was obtained, especially in entry 2 in Table 1 at 53% yield. To prevent β-elimination, the reaction was conducted at a lower temperature (0 °C) using Rh2Piv4,3g and the yield was improved up to 78% (48:52 (anti/syn)) (entry 5 in Table 1). Further reduction of the reaction temperature to −10 °C and −20 °C led to decreased yields (entries 6 and 7 in Table 1). The use of other metal triflates as Lewis acids also affected the reaction progress, but it did not generate higher yields than that obtained by the use of Yb(OTf)3 (entries 8−12 in Table 1). Finally, the investigation of catalyst loading of Yb(OTf)3 between 10 mol % and 30 mol % revealed that the highest yields (82%) were achieved at 10 mol % loading (entries 13 and 14 in Table 1). In addition, the reactions in the absence of Yb(OTf)3 (entry 15 in Table 1) or Rh2Piv4 (entry 16 in Table 1) were conducted as control experiments. As expected, no amino alcohols 5a were obtained under either condition, implying that a dual catalytic system consisting of Rh2Piv4 and a Lewis acid is crucial to the present 1,3-dipolar cycloadditions. The stereochemistry of 5a was determined by

entry

Rh complex

Lewis acid (mol %)

temperature (°C)

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

Rh2(OAc)4 Rh2(OAc)4 Rh2Piv4 Rh2Piv4 Rh2Piv4 Rh2Piv4 Rh2Piv4 Rh2Piv4 Rh2Piv4 Rh2Piv4 Rh2Piv4 Rh2Piv4 Rh2Piv4 Rh2Piv4 Rh2Piv4 none

Yb(OTf)3 (20) Yb(OTf)3 (20) Yb(OTf)3 (20) Yb(OTf)3 (20) Yb(OTf)3 (20) Yb(OTf)3 (20) Yb(OTf)3 (20) Cu(OTf)2 (20) Zn(OTf)2 (20) Mg(OTf)2 (20) Sc(OTf)3 (20) AgOTf (20) Yb(OTf)3 (30) Yb(OTf)3 (10) none Yb(OTf)3 (10)

25 25 25 25 0 −10 −20 0 0 0 0 0 0 0 0 0

yield (%) (anti/syn)b 44 33d 50 57 78 67 21 71 46 40 52 15e 65 82 0 0

(62:38) (53:47) (50:50) (52:48) (48:52) (42:58) (43:57) (51:49) (49:51) (58:42) (44:56) (62:38) (50:50) (46:54)

a

Unless otherwise noted, all reactions were carried out by adding a solution of 1a (0.75 mmol) in CH2Cl2 over a period of 12 h to a mixture of 2a (0.75 mmol), 3a (0.50 mmol), catalysts, and MS 4 A in CH2Cl2. bIsolated yield. The diastereomeric ratio (dr) of 5a was determined by 1H NMR analysis. cA solution of 1a in CH2Cl2 was added over a period of 1.5 h. d(Z)-Ethyl cinnamate was obtained in 53% yield (based on 1a). eDetermined by 1H NMR analysis using dibromomethane as an internal standard.

X-ray crystallographic analysis of syn-5a (see Supporting Information (SI)). Next, we investigated the reaction scope with respect to αalkyl-α-diazoesters, utilizing the corresponding benzyl esters (Scheme 3a). Although the optimum reaction temperature was dependent on the diazoesters, all substrates possessing an Me (1b), Et (1c), n-Bu (1d), or Bn (1e) group as an α-alkyl substituent on the α-carbon of 1 underwent the cycloadditions smoothly to afford amino alcohols 5b−5e in mostly good yields (67%−82%) after hydrolysis of the cycloadducts 4. The p-chlorobenzaldehyde- and p-tolualdehyde-derived imines were also tolerated to afford 5f and 5g by the reactions using 1b.10 Several α-aryl-α-diazoesters could also be used for the three-component reactions with aldehyde 2a and imine 3a employing the dual catalytic system [Rh2(OAc)4 (2 mol %) and Yb(OTf)3 (20 mol %)] to obtain the corresponding amino alcohols 6a−6e in high yields (90%−99%), even at 25 °C (Scheme 3b). Not only electron-deficient, but also electron-rich imines were tolerated in this system to afford 6f−6h in moderate to high yields. Again, it should be emphasized that the reaction of methyl α-phenyldiazoacetate, aldehyde 2a, and imine 3a only produced the epoxide in the absence of Lewis acid in the previous reports by Somfai et al.7b and Reddy et al.8 To confirm the effect of the Lewis acid, the reaction of 1f (R = Ph, R′ = Et), 2a, and 3a was also carried out in the absence of Yb(OTf)3 as a control B

DOI: 10.1021/acs.orglett.8b00865 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 3. Scope of Diazo Compounds 1 (R = Alkyl and Aryl) and Imines 3 for the Three-Component Reactions

Scheme 4. Three-Component Reactions of Dimethyl Diazomalonate (1k)a

a a

Unless otherwise noted, all reactions were carried out by adding a solution of 1k (1.5 mmol), 2 (1.5 mmol), and 3 (1.0 mmol) in CH2Cl2 to a mixture of Rh2Piv4 (2 mol %) and MS 4 A in CH2Cl2 at 25 °C. The yield was determined by 1H NMR analysis using 1,1,2,2tetrachloroethane as an internal standard (isolated yield is shown in parentheses). bThe reaction was carried out at 50 °C.

b

p-Chlorobenzaldehyde was used. N-(4-Methylbenzylidene)-4(methylbenzyl)amine was used. cp-Tolualdehyde was used.

experiment, leading to quantitative formation of the epoxide (>99% NMR yield; see the SI). X-ray structure analysis of syn6a was conducted to determine the relative stereochemistry of 6a, as well as 5a (see the SI). To broaden the scope of the diazo substrates, the threecomponent reactions using dimethyl diazomalonate (1k), aldehyde 2a, and imine 3a were investigated (Scheme 4). The reaction proceeded in the absence of a Lewis acid at 25 °C with the use of Rh2Piv4 (2 mol %) to afford trans-cycloadduct 7a as a single isomer in high yield.11,12 Cycloadduct 7a could be isolated in 76% yield by precipitation in a hexane-CH2Cl2 (16:1) mixed solvent from the unpurified material. The scope of aldehydes and imines was broad, providing trans-cycloadducts selectively in mostly high yields (see Scheme 4). In conclusion, we have established three-component reactions of α-alkyl-α-diazoesters, aromatic aldehydes, and N-benzylidenebenzylamines using a dual catalytic system consisting of Rh2Piv4 and Yb(OTf)3, affording amino alcohols in good yields after hydrolysis of the oxazolidine cycloadducts. The reactions proceeded via carbonyl ylide cycloadditions with imines, wherein the undesired β-hydrogen elimination

and the formation of the dioxolanes and the epoxides were suppressed with the help of the Rh/Yb catalysis. The threecomponent reactions using α-aryl-α-diazoesters and dimethyl diazomalonate have also been accomplished to broaden the reaction scope. Other types of 1,3-dipolar cycloadditions employing the dual catalytic system described herein are currently under investigation in our laboratory.

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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.8b00865. Experimental procedures and spectroscopic data for all new compounds (PDF) Accession Codes

CCDC 1831923, 1831931, and 1831933 contain the supplementary crystallographic data for this paper. These C

DOI: 10.1021/acs.orglett.8b00865 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

L.; Doyle, M. P. J. Org. Chem. 2004, 69, 5269−5274. (e) DeAngelis, A.; Panne, P.; Yap, G. P. A.; Fox, J. M. J. Org. Chem. 2008, 73, 1435−1439. For epoxide formation, see: (f) Doyle, M. P.; Hu, W.H.; Timmons, D. J. Org. Lett. 2001, 3, 933−935. (g) Davies, H. M. L.; DeMeese, J. Tetrahedron Lett. 2001, 42, 6803−6805. (5) (a) Nair, V.; Mathai, S.; Nair, S. M.; Rath, N. P. Tetrahedron Lett. 2003, 44, 8407−8409. (b) Nair, V.; Mathai, S.; Mathew, S. C.; Rath, N. P. Tetrahedron 2005, 61, 2849−2856. (c) Lu, C.-D.; Chen, Z.-Y.; Liu, H.; Hu, W.-H.; Mi, A.-O. Org. Lett. 2004, 6, 3071−3074. (d) Muthusamy, S.; Ramkumar, R.; Mishra, A. K. Tetrahedron Lett. 2011, 52, 148−150. (6) For the use of imines as dipolarophiles in the cycloadditions involving intramolecular ylide formation: (a) Padwa, A.; Precedo, L.; Semones, M. A. J. Org. Chem. 1999, 64, 4079−4088. (b) Muthusamy, S.; Krishnamurthi, J.; Suresh, E. Synlett 2005, 2005, 3002−3004. (c) Suga, H.; Ebiura, Y.; Fukushima, K.; Kakehi, A.; Baba, T. J. Org. Chem. 2005, 70, 10782−10791. (d) Gan, Y.; Harwood, L. M.; Richards, S. C.; Smith, I. E. D.; Vinader, V. Tetrahedron: Asymmetry 2009, 20, 723−725. (7) (a) Torssell, S.; Kienle, M.; Somfai, P. Angew. Chem., Int. Ed. 2005, 44, 3096−3099. (b) Torssell, S.; Somfai, P. Adv. Synth. Catal. 2006, 348, 2421−2430. (c) Xu, X.; Guo, X.; Han, X.; Yang, L.; Hu, W.-H. Org. Chem. Front. 2014, 1, 181−185. (8) Rajasekaran, T.; Sridhar, B.; Subba Reddy, B. V. Tetrahedron 2016, 72, 2102−2108. (9) (a) Padwa, A.; Dean, D. C.; Osterhout, M. H.; Precedo, L.; Semones, M. A. J. Org. Chem. 1994, 59, 5347−5357. (b) Rajasekaran, T.; Karthik, G.; Sridhar, B.; Subba Reddy, B. V. Org. Lett. 2013, 15, 1512−1515. (10) For further scope and limitations of α-alkyl-α-diazoesters, see the SI. (11) The structure and relative stereochemistry of 7n were determined by X-ray analysis, see the SI for details. (12) Rh2(OAc)4 (2 mol %) can also be used but more than 2 days were required for complete conversion of 1k.

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, U.K.; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Yasunori Toda: 0000-0001-9725-9438 Hiroyuki Suga: 0000-0001-8977-4691 Present Address †

Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108− 8641, Japan. Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108−8641, Japan. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported in part by the Japan Society for the Promotion of Science (JSPS) through a Grant-in-Aid for Scientific Research (C) (No. JP15K05497).

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REFERENCES

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DOI: 10.1021/acs.orglett.8b00865 Org. Lett. XXXX, XXX, XXX−XXX