Successive Waste as Reagent: Two More Steps Forward in a Pinnick

Feb 2, 2018 - As displayed in Table 1, the use of other hydrophilic solvents in the oxidative cyclization step had little effect on the reaction outco...
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Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Successive Waste as Reagent: Two More Steps Forward in a Pinnick Oxidation Yanjun Guo,† Chenhong Meng,† Xueli Liu,‡ Chen Li,† Aibao Xia,† Zhenyuan Xu,*,† and Danqian Xu*,† †

Catalytic Hydrogenation Research Center, State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou 310014, China ‡ School of Material and Chemical Engineering, Chuzhou University, Chuzhou 239000, China S Supporting Information *

ABSTRACT: The successful development of the classical Pinnick oxidation into a new and promising oxidative lactonization reaction is reported. Chiral 3-oxindolepropionic aldehydes, Michael adducts of 3-olefinic oxindoles with aliphatic aldehydes, are directly converted to spirocyclic oxindole-γ-lactones solely by sodium chlorite via a tandem Pinnick oxidation/chlorination/substitution sequence. This reaction uses waste ClO− generated in the initial Pinnick oxidation as an ecofriendly halogenating agent for the subsequent chlorination, and then it utilizes the byproduct OH− formed in the chlorination to facilitate the final internal substitution.

T

Scheme 1. Efforts for Adapting Pinnick Oxidation to Novel Oxidative Lactonization Reactions

he classical Pinnick oxidation is a mild and selective method for oxidizing aldehydes to carboxylic acids.1 In the mechanism of this reaction, once sodium chlorite (NaClO2) oxidizes the aldehydes into carboxylic acids, it is reduced to hypochlorite (ClO−), a more reactive chemical than ClO2−, that not only consumes the reactant NaClO2 but also causes other undesired reactions. Therefore, various scavengers such as resorcinol,1a sulfamic acid,1a 2-methyl-2-butene,1b and hydrogen peroxide1e must be added to the reaction to remove the ClO− as it is formed. Waste prevention is a crucial and challenging task in synthetic chemistry.2 Despite progress in designing one-pot tandem reactions that utilize byproducts, such as various inorganic salts (InCl3, CuI, NaF, and NaBr),3 Ph3PO,4 HCl,5 HI/I2,6 formed in the upstream step as catalyst or reagent for subsequent reactions, the use of waste ClO− formed in Pinnick oxidations as a reagent or catalyst has been rarely reported until we recently disclosed a NaClO2/DBDMH (1,3-dibromo-5.5dimethylhydantoin)-mediated γ-lactonization of γ,γ-dicarbonylsubstituted aldehydes. This reaction used waste ClO− as a useful chlorinating reagent, but its efficiency was limited, and DBDMH had to be added as a cohalogenating agent (Scheme 1, top).7 Clearly, developing a new Pinnick oxidation-initiated oxidative lactonization reaction in which waste ClO− is utilized as the only halogenating agent is highly attractive. Over the past decade, organocatalytic asymmetric Michaelinitiated one-pot reactions have attracted the attention of synthetic chemists,8 and chiral Michael adducts, namely, 3oxindolepropionic aldehydes, have been converted to diverse spiro cyclic oxindole scaffolds via [4 + 2] cycloadditions in onepot reactions.9 We demonstrate herein a new Michael-initiated one-pot reaction in which 3-oxindolepropionic aldehydes are converted to spirocyclic oxindole-γ-lactones,10 including spirocyclic oxindole−paraconic esters, solely by NaClO2 via a [4 + 1]-type cycloaddition (Scheme 1, middle). Paraconic acids11 are © XXXX American Chemical Society

naturally occurring γ-lactones with a carboxylic acid group in the β-position as their characteristic functionality, and they display both antibiotic and antitumor activities.12 Therefore, based on the structure−activity relationships used in drug design,13 spirocyclic oxindole−paraconic acids would be a new type of potentially bioactive compounds (Scheme 1, bottom). Our explorations began with the organocatalytic asymmetric Michael addition of propionaldehyde 2a to N-H free tert-butyl oxindolidene acetate 1a. In the presence of 2.5 mol % of secondary amine catalyst and 5 mol % of benzoic acid, 1a was smoothly consumed to give 3-oxindolepropionic aldehyde A. Delightfully, when NaClO2 was used as the only reagent, chiral aldehyde A was efficiently converted to product 3a in 94% yield with 93% ee and moderate diastereoselectivity (Table 1, entry 1). Received: November 28, 2017

A

DOI: 10.1021/acs.orglett.7b03684 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Optimization of Reaction Conditionsa

Scheme 2. Possible Mainstream Oxidative Lactonization Pathways and Working Mechanism

solvent entry

1

2

temp (°C)

yieldb (%)

drc

eed (%)

1 2 3 4 5 6 7

CH3CN CH3CN CH3CN CH3CN toluene CH3CN CH3CN

acetone tBuOH THF CH3CN acetone acetone acetone

25 25 25 25 25 0 −30

94 95 93 93 90 94 95

75:12:12:1 71:14:14:1 70:15:14:1 71:15:13:1 62:19:18:1 74:13:11:2 76:12:10:2

93 92 92 93 90 93 99

a

Boc = tert-butoxycarbonyl; 1a (1.0 mmol), 2a (2 equiv), cat. (2.5 mol %), BA = benzoic acid (5 mol %), solvent 1 (2.0 mL); solvent 2 (4 mL). bIsolated yields. c,dDetermined by chiral HPLC.

The effects of solvent and reaction temperature on this new onepot reaction were investigated. As displayed in Table 1, the use of other hydrophilic solvents in the oxidative cyclization step had little effect on the reaction outcome (entry 2−4). When the solvent for the Michael addition step was changed from CH3CN to toluene, relatively poor results were observed (entry 5). When the reaction temperature was decreased to −30 °C, the enantiomeric excess improved to 99% (entry 7). However, carrying out the reaction at 0 °C had no effect on the reaction outcome relative to that of the room temperature reaction (entry 6 and 1). It is noteworthy that the diastereomeric ratio was improved by conversion of the 3-oxindolepropionic aldehyde A (63:25:6:6 dr) to spirocyclic oxindole−paraconic ester 3a (76:12:10:2 dr). On the basis of the reaction results, LC−HRMS analysis of the reaction mixture (details in the Supporting Information), and previous reports involving α-chlorinations of β-1,3-dicarbonyl compounds using hypochlorite under alkaline conditions,14 the possible oxidative lactonization pathways and working mechanism for the solely NaClO2-mediated oxidative spirolactonization of 3-oxindolepropionic aldehyde A is depicted in Scheme 2.15 Initially, 1 equiv of aldehyde A was oxidized to carboxylic acid B1 by NaClO2, which was concomitantly reduced to ClO−. Then, the in situ generated ClO − reacted with either intermediate B1 or A via electrophilic chlorination to afford new intermediates C and B2, respectively. Similarly, 3chlorooxindolepropionic aldehyde B2 was oxidized to 3chlorooxindolepropionic acid C by NaClO2. Finally, intermediate C was converted to product 3a via an internal nucleophilic substitution, which was promoted by the OH− formed in the chlorination step. Subsequently, the scope of this new one-pot reaction was examined by first using readily available and variously substituted N-H free or N-Boc-protected tert-butyl oxindolideneacetates (Table 2). N-H free substrates reacted smoothly to afford the corresponding products (3a−k) in high yields. For the N-Bocprotected substrates, strong electronic effects were observed for the oxidative lactonization process; substrates containing electron-donating groups (3l,m) were tolerated well, but substrates containing electron-withdrawing or halogen groups (3n−p) gave the products in moderate yields. This effect is likely due to the low electron density at the C3 site of the oxindole, which disfavors the in situ generated ClO−-mediated electro-

Table 2. Substituent Effects of N-H Free or N-Boc-Protected tert-Butyl Oxindolideneacetatesa

entry

R1

PG

3

yield (%)

dr

ee (%)

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

H 5-Me 5-F 5-Cl 5-Br 6-Cl 6-Br 7-F 7-Cl 7-Br 7-CF3 H 5-Me 5-F 6-Cl 7-F

H H H H H H H H H H H Boc Boc Boc Boc Boc

3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o 3p

95 (50) 93 (36) 97 (32) 95 (52) 94 (47) 95 (44) 94 (41) 89 (51) 91 (55) 92 (61) 91 (57) 93 (50) 95 (46) 47 59 44

76:12:10:2 76:13:10:1 78:11:10:1 87:11:1:1 80:11:9:0 77:11:11:1 77:14:8:1 83:11:6:0 84:9:7:0 87:8:5:0 87:8:5:0 83:14:2:1 84:13:2:1 ND ND ND

99 98 97 98 98 98 97 99 97 99 97 99 99 ND ND ND

a

The data in parentheses are the isolated yields of the major stereoisomers (>20:1 dr), which were obtained by recrystallization. ND = not determined.

philic chlorination process. N-Me- or N-Bn-protected substrates were then tested (Table 3). Notably, to obtain satisfactory enantioselectivities, the catalyst and solvent used in the Michael step had to be changed. Unlike the above-mentioned N-BocB

DOI: 10.1021/acs.orglett.7b03684 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 3. Substituent Effects of N-Me- or N-Bn-Protected tertButyl Oxindolideneacetatesa,b

entry

R1

PG

3

yield (%)

dr

ee (%)

1 2 3 4 5 6 7 8 9 10

5-Cl 5-Cl 5-F 5-Br 5-I 5-CF3O 6-Cl 7-CF3 H 5-MeO

Me Bn Me Me Me Me Me Me Me Me

3q 3r 3s 3t 3u 3v 3w 3x 3y 3z

92 (40) 78 (28) 90 (28) 95 (45) 90 (46) 87 (50) 92 (42) 89 (51) 53 42

76:15:9:0 78:22:0:0 65:21:14:0 74:15:10:1 77:12:9:2 86:11:3:0 75:13:9:3 86:11:3:0 ND ND

97 97 95 98 97 97 97 94 ND ND

moving from propionaldehydes to other aliphatic aldehydes, the diversity of the spirooxindole skeletons was further expanded (3ze−zf). Furthermore, tert-butyl (E)-2-(2-oxobenzofuran3(2H)-ylidene)acetate 1zg was also tested. The first Michael addition step proceeded well, but the subsequent oxidative spirolactonization process was dramatically suppressed in this system and gave rare spirocyclic benzofuran−paraconic ester 3zg in 32% yield (eq 1). The result implies that a more efficient spirolactonization system should be developed to improve the yield.

To assess the practicality of this new methodology, the onepot reaction was performed on a gram scale and gave product 3a in 92% yield with 98% ee and moderate diastereoselectivity (Scheme 3, top). To our delight, excellent diastereomeric excess

a

Ar = 3,5-(CF3)2-C6H3. bThe data in parentheses are the isolated yields of the major stereoisomers (>20:1 dr), which were obtained by recrystallization. ND = not determined.

Scheme 3. Gram-Scale Reaction and Synthetic Application protected substrates, reactions with substrates containing electron-withdrawing or halogen groups (3q−x) proceeded smoothly. However, electron-donating groups (3y−z) were not well tolerated in the oxidative lactonization process; this is probably due to the electron-donating substituents on the benzene rings disfavoring the enolization of the N-Me-protected oxindole and the crucial chlorination step. Encouragingly, most of the spirocyclic oxindole-paraconic esters (3a−z) were obtained in almost diastereopure form and moderate yields via recrystallization. Moreover, the absolute configuration of 3o was confirmed by single-crystal X-ray structural analysis. To further expand the diversity of the spirocyclic oxindoles, other 3-olefinic oxindoles and aliphatic aldehydes were investigated. As shown in Table 4, the 3-ylideneoxindoles with methyl and ethyl esters were also good substrates for the reaction (3za−zb). Regrettably, it was hard to obtain diastereopure 3za via simple recrystallization. Moderate yields and diastereoselectivities were obtained for 3-keto-olefinic oxindoles, but the enantioselectivities remained good to excellent (3zc−zd). By

was achieved after a simple recrystallization. A synthetic transformation experiment was then conducted (Scheme 3, bottom). The Boc group was readily hydrolyzed by trifluoroacetic acid (TFA) in DCM over 12 h, which furnished spirocyclic oxindole−paraconic acid 4 in 94% yield. Note that this hydrolysis resulted in no erosion of the enantiomeric excess. In conclusion, we developed a new Michael-initiated one-pot reaction, and a conventional Pinnick oxidation was successfully adapted into a novel and ecofriendly oxidative lactonization reaction by a “successive waste as reagent” strategy. This new reaction provides chiral spirocyclic oxindole−paraconic acid derivatives and other spirocyclic γ-lactones that bear rare three chiral stereocenters in up to 97% yield with up to 99% ee. Importantly, most of the major stereoisomers are obtained in acceptable yields by simple recrystallization. The biological evaluation of the spirocyclic oxindole−paraconic acids and their derivatives, as well as efforts toward other oxidative lactonization reactions involving NaClO2, are currently underway and will be reported in due course.

Table 4. Further Exploration of Reaction Scopea

entry

R2

R3

3

yield (%)

dr

ee (%)

1 2 3 4 5 6

MeO EtO Me Ph t-BuO t-BuO

Me Me Me Me Et n-Pr

3za 3zb 3zc 3zd 3ze 3zf

89 89 (20) (32) (23) 97 (58) 90 (45)

71:14:10:5 71:14:11:4 63:25:7:5 59:32:6:3 79:12:7:2 72:17:6:5

95 96 88 97 99 98

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ASSOCIATED CONTENT

* Supporting Information

a

For 3zb, 3ze, and 3zf, the data in parentheses are the isolated yields of the major stereoisomers (>20:1 dr), which were obtained by recrystallization. For 3zc and 3zd, the data in parentheses are the isolated yields of the major stereoisomers, which were isolated by column chromatography.

S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03684. Experimental details, analytical data, NMR spectra (PDF) C

DOI: 10.1021/acs.orglett.7b03684 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Accession Codes

(9) (a) Bencivenni, G.; Wu, L.-Y.; Mazzanti, A.; Giannichi, B.; Pesciaioli, F.; Song, M.-P.; Bartoli, G.; Melchiorre. Angew. Chem., Int. Ed. 2009, 48, 7200. (b) Jiang, K.; Jia, Z.-J.; Chen, S.; Wu, L.; Chen, Y.-C. Chem. - Eur. J. 2010, 16, 2852. (c) Zhu, L.-Y.; Chen, Q.-L.; Shen, D.; Zhang, W.-H.; Shen, C.; Zeng, X.-F.; Zhong, G.-F. Org. Lett. 2016, 18, 2387. (d) Tan, Y.; Feng, E.-L.; Sun, Q.-S.; Lin, H.; Sun, X.; Lin, G.-Q.; Sun, X.-W. Org. Biomol. Chem. 2017, 15, 778. (10) For selected examples of construction of spirocyclic oxindole-γlactones, see: (a) Reddi, Y.; Sunoj, R. B. ACS Catal. 2017, 7, 530. (b) Chen, X.-Y.; Chen, K.-Q.; Sun, D.-Q.; Ye, S. Chem. Sci. 2017, 8, 1936. (c) Zhou, R.; Liu, R.-F.; Zhang, K.; Han, L.; Zhang, H.-H.; Gao, W.-C.; Li, R.-F. Chem. Commun. 2017, 53, 6860. (d) Li, G.-F.; Huang, L.W.; Xu, J.-C.; Sun, W.-S.; Xie, J.-Q.; Hong, L.; Wang, R. Adv. Synth. Catal. 2016, 358, 2873. (e) Chen, L.; Wu, Z.-J.; Zhang, M.-L.; Yue, D.-F.; Zhang, X.-M.; Xu, X.-Y.; Yuan, W.-C. J. Org. Chem. 2015, 80, 12668. (f) Xie, Y.-W.; Yu, C.-X.; Li, T.-J.; Tu, S.-J.; Yao, C.-S. Chem. - Eur. J. 2015, 21, 5355. (g) Zheng, C.-G.; Yao, W.-J.; Zhang, Y.-C.; Ma, C. Org. Lett. 2014, 16, 5028. (h) Wang, Q.-L.; Peng, L.; Wang, F.-Y.; Zhang, M.L.; Jia, L.-N.; Tian, F.; Xu, X.-Y.; Wang, L.-X. Chem. Commun. 2013, 49, 9422. (i) Bergonzini, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2012, 51, 971. (j) Dugal-Tessier, J.; O’Bryan, E. A.; Schroeder, T. B. H.; Cohen, D. T.; Scheidt, K. A. Angew. Chem., Int. Ed. 2012, 51, 4963. (11) For a review on paraconic acids, see: Bandichhor, R.; Reiser, O. Top. Curr. Chem. 2005, 243, 43. (12) Kumar KC, S.; Müller, K. Lichen Metabolites. 1. Inhibitory Action Against Leukotriene B4 Biosynthesis by a Non-Redox Mechanism. J. Nat. Prod. 1999, 62, 817. (13) (a) Rana, S.; Blowers, E. C.; Tebbe, C.; Contreras, J. I.; Radhakrishnan, P.; Kizhake, S.; Zhou, T.; Rajule, R.-N.; Arnst, J.-L.; Munkarah, A.-R.; Rattan, R.; Natarajan, A. J. Med. Chem. 2016, 59, 5121. (b) Dudek, A. Z.; Arodz, T.; Galvez, J. Comb. Chem. High Throughput Screening 2006, 9, 213. (c) Buchwald, P.; Bodor, N. Drugs Future 2002, 27, 577. (14) (a) Straus, F.; Kühnel, R. Ber. Dtsch. Chem. Ges. B 1933, 66, 1834. (b) Baldovini, N.; Bertrand, M. P.; Carriere, A.; Nouguier, R.; Plancher, J. M. J. Org. Chem. 1996, 61, 3205. (15) We thank a reviewer for proposing an alternative pathway to 3a from aldehyde A. This possibility cannot be ruled out and is depicted below:

CCDC 1469566 contains 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 data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

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

Yanjun Guo: 0000-0002-9136-7486 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from the National Natural Science Foundation of China (21402176), the Natural Science Foundation of Zhejiang Province (LY14B020003), and the National Key R&D Program of China (2017YFB0307203). We also thank A.P. Renrong Liu, Xiaoji Cao, and Dr. Renxiao Liang (ZJUT) for their helpful discussions.

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DOI: 10.1021/acs.orglett.7b03684 Org. Lett. XXXX, XXX, XXX−XXX