Zinc-Mediated Decarboxylative Alkylation of Gem-difluoroalkenes

Jun 15, 2018 - The Institutes of Integrative Medicine of Fudan University, Shanghai 201203, China. ‡ ... The reaction tolerates a broad range of fun...
0 downloads 0 Views 1MB Size
Download PDF
Letter pubs.acs.org/OrgLett

Cite This: Org. Lett. 2018, 20, 4579−4583

Zinc-Mediated Decarboxylative Alkylation of Gem-difluoroalkenes Liting Yu,†,‡ Mei-Lin Tang,† Chang-Mei Si,† Zhi Meng,† Yongxi Liang,† Jilai Han,† and Xun Sun*,†,§ †

Department of Natural Products Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China The Institutes of Integrative Medicine of Fudan University, Shanghai 201203, China ‡ Otsuka Shanghai Research Institute, Shanghai 201203, China §

Downloaded via NORTHWESTERN UNIV on August 3, 2018 at 19:12:13 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: An efficient and mild zinc-mediated decarboxylative alkylation of gem-difluoroalkenes with N-hydroxyphthalimide (NHP) esters, to give monofluoroalkenes in moderate to excellent yields with high Z-selectivity is reported. The reaction tolerates a broad range of functional groups and can be easily scaled up, which thus may pave the way for its further applications in medicinal chemistry and materials science. to medicinal chemistry,12 here, we report the first zincmediated decarboxylative defluoroalkylation that is scalable and widely adaptable across a range of gem-difluoroalkenes and alkyl NHP esters, to afford a large array of monofluoroalkenes under mild conditions (see Scheme 1).

M

onofluoroalkenes are one of topical biomedicinal interest, as such a moiety that can strongly mimic an amide bond, thereby improving the molecule metabolic stability and lipophilicity.1 Over the past decade, some elegant approaches have been developed en route to the synthesis of this type of compounds.2 However, monofluoroalkene formation via direct defluoroalkylation3 and defluoroarylation4 of gem-difluoroalkene or indirectly defluoroborylation5 and Suzuki coupling is only a recent event and still remains much less explored. In 2016, Cao’s group developed a defluoroalkylation of gem-difluoroalkenes with Grignard reagents under Cu-catalysis or metal-free conditions.3a Hashmi’s group reported a photocatalytic defluoroalkylation of gem-difluoroalkenes with amine or aniline derivatives.3b Recently, Fu, Gong, and their co-workers reported a Ni-catalyzed defluoroalkylation with alkyl iodide or bromide as the alkylating agents.3c Fu’s group reported a photoinduced decarboxylative monofluoroalkylation of amino acid with gem-difluoroalkenes.3d Very recently, Wang and Li extended this protocol via Fe-catalyzed defluorinative cross-coupling of alkene with gemdifluoroalkenes.3e Despite these remarkable achievements, however, defluoroalkylation protocols are still plagued by the moderate Z/E selectivity and/or the use expensive catalysts or air-sensitive reagents. In this context, further development of more convenient and scalable procedures with a broad substrate scope and using readily accessible reagents/starting materials, is highly desirable for practical synthesis of monofluoroalkenes. On the other hand, decarboxylative functionalization with NHP esters has become a hot topic in recent years. These esters are easily synthesized from naturally abundant or commercially available carboxylic acids, and they can readily generate the corresponding alkyl or aryl radicals upon receiving an electron and releasing CO2. The resulting radicals are highly reactive intermediates, readily engaging in borylation,6 alkenylation,7 arylation,8 alkynylation,9 cyanation,10 and other reactions.11 As part of our continuing pursuit for bioactive fluorine-containing molecules with potential value © 2018 American Chemical Society

Scheme 1. Defluoroalkylation of gem-Difluoroalkenes

The study was initiated by examining the reaction of gemdifluorostyrene 1a and NHP ester 2a. An extensive screen of various parameters, including metals (Zn, Mn, Cu, Fe), solvents (DMA, DMF, NMP, DMSO), substrate concentrations, and additives (water, 4A MS), revealed that the reaction was best conducted in DMA (0.67 M) at room temperature (rt), using 3 equiv of zinc powder as the reductant. Under these optimized conditions, the reaction of 1a (1 equiv) and 2a (3 equiv) afforded 3aa in 83% yield (for details, see the Supporting Information (SI)). Encouraged by this result, we proceeded to examine the scope of the reaction, Received: June 15, 2018 Published: July 19, 2018 4579

DOI: 10.1021/acs.orglett.8b01866 Org. Lett. 2018, 20, 4579−4583

Letter

Organic Letters

Scheme 3. Substrate Scope of gem-Difluoroalkene and NHP Estersa

with respect to NHP esters, for defluoroalkylation of 1a with zinc as the reductant. As shown in Scheme 2, a variety of NHP Scheme 2. Substrate Scope of NHP estersa

a Conditions: 1a (0.2 mmol, 1 equiv), 2 (0.6 mmol, 3 equiv), Zn (0.6 mmol, 3 equiv), DMA (0.3 mL), under N2, rt, isolated yields. The Z/E ratios were determined by 19F NMR and 1H NMR of the isolated products.

esters, including sterically hindered secondary and tertiary NHP esters, were readily converted to the corresponding defluoroalkylation products 3aa−3aq in good to excellent yields (61%−96%) with uniformly high Z-stereoselectivity. It is noteworthy that racemic α-amino-acid-derived NHP esters 2j−2o also reacted smoothly to furnish the corresponding products 3aj−3ao in high yields. Subsequently, we further evaluated the reaction scope by modulating both gemdifluoroalkenes and NHP esters. As shown in Scheme 3, the protocol proved to be quite versatile, and various gemdifluoroalkenes reacted smoothly with a broad range of primary, secondary, or tertiary NHP esters, affording the corresponding defluoroalkylation products containing diverse functional groups in moderate to good yields. For example, the protocol was very compatible with Pd/Ni sensitive groups, such that iodo (3nq), bromo (3cc, 3ea, 3ol, 3ep, 3fp, 3gp, and 3gq) and chloro (3jp and 3jq) attached to sp2-carbons remained intact during the reactions. Various heterocyclic moieties, including indolyl (3cc), benzothienyl (3dc, 3dr, 3ds, 3dv, 3dt, 3dw, 3dp, and 3kq), pyridyl (3lm, 3mm, 3lq, and 3mq), and thienyl (3ol and 3dw), were all tolerated in the reaction under such mild conditions, which is an attractive feature for synthetic applications in medicinal chemistry. Interestingly, other type of gem-difluoroalkenes also gave the product 3qc and tetra-substituted monofluoroalkenes 3pa, 3si, and 3ra in moderate to good yields with moderate to excellent Z-selectivities. It is notable that the monofluoroalkenes 3ea,

a

Conditions: 1 (0.2 mmol, 1 equiv), 2 (0.6 mmol, 3 equiv), Zn (0.6 mmol, 3 equiv), DMA (0.3 mL), under N2, rt, isolated yields. bThe reaction was conducted with 2 mmol of 1e. cThe reaction was scaled up to 10-fold. dThe reaction was scaled up to 20-fold.

3ol, and 3ep were readily synthesized on a 2−4 mmol scale using this procedure without compromising the yields (53%− 81%). To demonstrate the synthetic utility of the protocol, the defluoroalkylation was scaled up with no difficulty to 66.7 mmol (15 g) of 1o with 2l (74.8 g), delivering the 4580

DOI: 10.1021/acs.orglett.8b01866 Org. Lett. 2018, 20, 4579−4583

Letter

Organic Letters corresponding product 3ol in good yield (17 g, 65%) (see Scheme 4a). One-pot synthesis of 3ol, starting from carboxylic

Scheme 5. Control Experiments

Scheme 4. Scale-Up Reactions and Synthetic Application

radical nature of the reaction (see Scheme 6a). Similarly, reaction of NHP ester 2a′ with 1a afforded 3aa′ as the exclusive product in 50% yield (see Scheme 6b). Moreover, the possible catalysis by other metals, such as Rh, Cu, Ni, Co, Fe, Cr, Sn, or Pb, can be excluded by ICP-AES analysis, which indicated the absence of these elements in the zinc powder

a

NHP = N-hydroxyphthalimide, DIC = 1,3-diisopropylcarbodiimide, DMAP = 4-dimethylaminopyridine. bHATU = 1-[Bis(dimethylamino)methylene]-1H-1, 2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate.

Scheme 6. Mechanistic Investigation

acid precursor 4 and without purification and isolation of its NHP ester 2l, was also successful and gave product 3ol in yields similar to that obtained using standard protocol, which largely simplified the workup procedure (Scheme 4b). Further synthetic manipulation of the defluoroalkylation product was conducted on 3ep, which was coupled with phenyl boronic acid under Suzuki conditions to afford the biphenyl product 5 in 95% yield. Subsequent hydrolysis of 5 under alkaline conditions and condensation with morpholine afforded the amide 6, whose structure was confirmed by X-ray crystallographic analysis (see Scheme 4c). According to the report by Fu and Gong,3c both secondary alkyl iodide and tertiary alkyl bromide reacted easily with gemdifluorostyrene under the Ni(COD)2 catalysis. In contrast, for the reaction of 1a with adamantyl bromide 7 under our standard conditions, 3ae could hardly be observed (see Scheme 5a). Moreover, reactions of 2x with 1a or 2y with 1d afforded the corresponding decarboxylative coupling product 3ax and 3dy in 80% and 53% yield, respectively (see Schemes 5b and 5c), with the bromine moiety remaining intact during the reaction, and these reactions provide a useful handle for further synthetic elaborations of this halogen. To gain some insights into the mechanism of this reaction, 1a was stirred under standard conditions in the absence of NHP ester, and no reaction occurred. In addition, two radical clock experiments were also conducted. When NHP ester 2z was reacted with 1d under standard conditions, 3dz was isolated as the only product, albeit in 40% yield, suggesting the 4581

DOI: 10.1021/acs.orglett.8b01866 Org. Lett. 2018, 20, 4579−4583

Letter

Organic Letters

(2) (a) Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119. (b) Landelle, G.; Bergeron, M.; Turcotte-Savard, M.-O.; Paquin, J.-F. Chem. Soc. Rev. 2011, 40, 2867. (c) Zhang, X.; Cao, S. Tetrahedron Lett. 2017, 58, 375. (d) Yanai, H.; Taguchi, T. Eur. J. Org. Chem. 2011, 2011, 5939. (e) Zhang, W.; Huang, W.; Hu, J. Angew. Chem., Int. Ed. 2009, 48, 9858. (f) Schneider, C.; Masi, D.; Couve-Bonnaire, S.; Pannecoucke, X.; Hoarau, C. Angew. Chem., Int. Ed. 2013, 52, 3246. (g) Vandamme, M.; Paquin, J.-F. Org. Lett. 2017, 19, 3604. (h) Hu, J.; Han, X.; Yuan, Y.; Shi, Z. Angew. Chem., Int. Ed. 2017, 56, 13342. (i) Kojima, R.; Kubota, K.; Ito, H. Chem. Commun. 2017, 53, 10688. (3) (a) Dai, W.; Shi, H.; Zhao, X.; Cao, S. Org. Lett. 2016, 18, 4284. (b) Xie, J.; Yu, J.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Angew. Chem., Int. Ed. 2016, 55, 9416. (c) Lu, X.; Wang, Y.; Zhang, B.; Pi, J.J.; Wang, X.-X.; Gong, T.-J.; Xiao, B.; Fu, Y. J. Am. Chem. Soc. 2017, 139, 12632. (d) Li, J.; Lefebvre, Q.; Yang, H.; Zhao, Y.; Fu, H. Chem. Commun. 2017, 53, 10299. (e) Yang, L.; Ji, W.-W.; Lin, E.; Li, J.-L.; Fan, W.-X.; Li, Q.; Wang, H. Org. Lett. 2018, 20, 1924. (4) (a) Fuchibe, K.; Mayumi, Y.; Zhao, N.; Watanabe, S.; Yokota, M.; Ichikawa, J. Angew. Chem., Int. Ed. 2013, 52, 7825. (b) Tian, P.; Feng, C.; Loh, T.-P. Nat. Commun. 2015, 6, 7472. (c) Xiong, Y.; Huang, T.; Ji, X.; Wu, J.; Cao, S. Org. Biomol. Chem. 2015, 13, 7389. (d) Thornbury, R. T.; Toste, F. D. Angew. Chem., Int. Ed. 2016, 55, 11629. (e) Kong, L.; Zhou, X.; Li, X. Org. Lett. 2016, 18, 6320. (f) Zhang, B.; Zhang, X.; Hao, J.; Yang, C. Org. Lett. 2017, 19, 1780. (g) Zell, D.; Dhawa, U.; Müller, V.; Bursch, M.; Grimme, S.; Ackermann, L. ACS Catal. 2017, 7, 4209. (h) Gong, T.-J.; Xu, M.-Y.; Yu, S.-H.; Yu, C.-G.; Su, W.; Lu, X.; Xiao, B.; Fu, Y. Org. Lett. 2018, 20, 570. (i) Wu, J.-Q.; Zhang, S.-S.; Gao, H.; Qi, Z.; Zhou, C.-J.; Ji, W.-W.; Liu, Y.; Chen, Y.; Li, Q.; Li, X.; Wang, H. J. Am. Chem. Soc. 2017, 139, 3537. (5) (a) Zhang, J.; Dai, W.; Liu, Q.; Cao, S. Org. Lett. 2017, 19, 3283. (b) Tan, D. H.; Lin, E.; Ji, W. W.; Zeng, Y. F.; Fan, W. X.; Li, Q.; Gao, H.; Wang, H. Adv. Synth. Catal. 2018, 360, 1032. (c) Sakaguchi, H.; Uetake, Y.; Ohashi, M.; Niwa, T.; Ogoshi, S.; Hosoya, T. J. Am. Chem. Soc. 2017, 139, 12855. (6) (a) Li, C.; Wang, J.; Barton, L. M.; Yu, S.; Tian, M.; Peters, D. S.; Kumar, M.; Yu, A. W.; Johnson, K. A.; Chatterjee, A. K.; Yan, M.; Baran, P. S. Science 2017, 356, eaam7355. (b) Fawcett, A.; Pradeilles, J.; Wang, Y.; Mutsuga, T.; Myers, E. L.; Aggarwal, V. K. Science 2017, 357, 283. (c) Candish, L.; Teders, M.; Glorius, F. J. Am. Chem. Soc. 2017, 139, 7440. (d) Hu, D.; Wang, L.; Li, P. Org. Lett. 2017, 19, 2770. (e) Cheng, W.-M.; Shang, R.; Zhao, B.; Xing, W.-L.; Fu, Y. Org. Lett. 2017, 19, 4291. (7) (a) Edwards, J. T.; Merchant, R. R.; McClymont, K. S.; Knouse, K. W.; Qin, T.; Malins, L. R.; Vokits, B.; Shaw, S. A.; Bao, D. H.; Wei, F. L.; Zhou, T.; Eastgate, M. D.; Baran, P. S. Nature 2017, 545, 213. (b) Suzuki, N.; Hofstra, J. L.; Poremba, K. E.; Reisman, S. E. Org. Lett. 2017, 19, 2150. (8) (a) Huihui, K. M. M.; Caputo, J. A.; Melchor, Z.; Olivares, A. M.; Spiewak, A. M.; Johnson, K. A.; DiBenedetto, T. A.; Kim, S.; Ackerman, L. K. G.; Weix, D. J. J. Am. Chem. Soc. 2016, 138, 5016. (b) Proctor, R. S. J.; Davis, H. J.; Phipps, R. J. Science 2018, 360, 419. (c) Toriyama, F.; Cornella, J.; Wimmer, L.; Chen, T.-G.; Dixon, D. D.; Creech, G.; Baran, P. S. J. Am. Chem. Soc. 2016, 138, 11132. (d) Cheng, W.-M.; Shang, R.; Fu, M.-C.; Fu, Y. Chem. - Eur. J. 2017, 23, 2537. (9) (a) Huang, L.; Olivares, A. M.; Weix, D. J. Angew. Chem., Int. Ed. 2017, 56, 11901. (b) Smith, J. M.; Qin, T.; Merchant, R. R.; Edwards, J. T.; Malins, L. R.; Liu, Z.; Che, G.; Shen, Z.; Shaw, S. A.; Eastgate, M. D.; Baran, P. S. Angew. Chem., Int. Ed. 2017, 56, 11906. (10) Wang, D.; Zhu, N.; Chen, P.; Lin, Z.; Liu, G. J. Am. Chem. Soc. 2017, 139, 15632. (11) For selected articles, see: (a) Xuan, J.; Zhang, Z.-G.; Xiao, W.-J. Angew. Chem., Int. Ed. 2015, 54, 15632. (b) Patra, T.; Maiti, D. Chem. - Eur. J. 2017, 23, 7382. (c) Larsen, C. B.; Wenger, O. S. Chem. - Eur. J. 2018, 24, 2039. (d) Kaga, A.; Chiba, S. ACS Catal. 2017, 7, 4697. (e) Schwarz, J.; Konig, B. Green Chem. 2018, 20, 323. (f) Jin, Y.; Fu, H. Asian J. Org. Chem. 2017, 6, 368. (g) Schnermann, M. J.; Overman,

reagent. Based on these results, a plausible mechanism with radical type intermediates was proposed for the titled reaction (see Scheme 6c).3 Single-electron transfer (SET) from zinc to the NHP ester would result in fragmentation of the radical anion A to a stabilized NHP− anion and a carboxyl radical, which readily undergo a Barton decarboxylation to generate the R• radical. The gem-difluoroalkene would undergo a nucleophilic attack by radical R•, to afford radical intermediate B that is reduced by Zn+ to anion C in a second SET process. Extrusion of a fluoride from C via a conformationally favorable anticoplanar pathway would give the Z-monofluoroalkene 3. In summary, a mild, scalable, and general method has been developed for the decarboxylative defluoroalkylation of gemdifluoroalkenes with NHP esters using zinc powder as the reductant, to furnish a wide range of monofluoroalkenes in good to high yields and excellent Z-selectivities. The reaction tolerates a broad scope of functional groups and can be easily scaled up, which hold promise for practical synthetic applications. Preliminary mechanistic studies strongly supported the radical nature of the reaction. Further studies are underway in our laboratories.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01866. Experimental procedure, characterization of all new compounds and results of in situ NMR (PDF) Accession Codes

CCDC 1832289 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, U.K.; fax: + 44 1223 336033.

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Xun Sun: 0000-0002-4316-2988 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS Financial support was provided by the National Natural Science Foundation of China (No. 81673297) and the Shanghai Municipal Committee of Science and Technology (Nos. 17JC1400200 and 17431902500).

■

REFERENCES

(1) (a) Lin, G.-Q.; You, Q.-D.; Cheng, J.-F. Chiral Drugs: Chemistry and Biological Action; John Wiley & Sons, Inc. 2011. (b) Meanwell, N. A. J. Med. Chem. 2018, DOI: 10.1021/acs.jmedchem.7b01788. (c) Oishi, S.; Kamitani, H.; Kodera, Y.; Watanabe, K.; Kobayashi, K.; Narumi, T.; Tomita, K.; Ohno, H.; Naito, T.; Kodama, E.; Matsuoka, M.; Fujii, N. Org. Biomol. Chem. 2009, 7, 2872. (d) Asahina, Y.; Iwase, K.; Iinuma, F.; Hosaka, M.; Ishizaki, T. J. Med. Chem. 2005, 48, 3194. (e) Couve-Bonnaire, S.; Cahard, D.; Pannecoucke, X. Org. Biomol. Chem. 2007, 5, 1151. 4582

DOI: 10.1021/acs.orglett.8b01866 Org. Lett. 2018, 20, 4579−4583

Letter

Organic Letters L. E. Angew. Chem., Int. Ed. 2012, 51, 9576. (h) Zhao, W.; Wurz, R. P.; Peters, J. C.; Fu, G. C. J. Am. Chem. Soc. 2017, 139, 12153. (i) Xue, W.; Oestreich, M. Angew. Chem., Int. Ed. 2017, 56, 11649. (j) Okada, K.; Okamoto, K.; Oda, M. J. Am. Chem. Soc. 1988, 110, 8736. (k) Sha, W.; Ni, S.; Han, J.; Pan, Y. Org. Lett. 2017, 19, 5900. (l) Yang, J.-C.; Zhang, J.-Y.; Zhang, J.-J.; Duan, X.-H.; Guo, L.-N. J. Org. Chem. 2018, 83, 1598. Xia, Z.-H.; Zhang, C.-L.; Gao, Z.-H.; Ye, S. Org. Lett. 2018, 20, 3496. (12) (a) Wang, M.; Liu, X.; Zhou, L.; Zhu, J.; Sun, X. Org. Biomol. Chem. 2015, 13, 3190. (b) Lu, H.-F.; Xie, C.; Chang, J.; Lin, G.-Q.; Sun, X. Eur. J. Med. Chem. 2011, 46, 1743. (c) Xie, C.; Chang, J.; Hao, X.-D.; Yu, J.-M.; Liu, H.-R.; Sun, X. Eur. J. Pharm. Biopharm. 2013, 85, 541. (d) Lu, H.-F.; Sun, X.; Xu, L.; Lou, L.-G.; Lin, G.-Q. Eur. J. Med. Chem. 2009, 44, 482.

4583

DOI: 10.1021/acs.orglett.8b01866 Org. Lett. 2018, 20, 4579−4583