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International Edition: DOI: 10.1002/anie.201706611 German Edition: DOI: 10.1002/ange.201706611
Cross-Coupling
Copper-Catalyzed Decarboxylative Radical Silylation of Redox-Active Aliphatic Carboxylic Acid Derivatives Weichao Xue and Martin Oestreich* Abstract: A decarboxylative silylation of aliphatic N-hydroxyphthalimide (NHPI) esters using Si@B reagents as silicon pronucleophiles is reported. This C(sp3)@Si cross-coupling is catalyzed by copper(I) and follows a radical mechanism, even with exclusion of light. Both primary and secondary alkyl groups couple effectively, whereas tertiary alkyl groups are probably too sterically hindered. The functional-group tolerance is generally excellent, and a-heteroatom-substituted substrates also participate well. This enables, for example, the synthesis of a-silylated amines starting from NHPI esters derived from a-amino acids. The new method extends the still limited number of C(sp3)@Si cross-couplings of unactivated alkyl electrophiles.
The cross-coupling of unactivated alkyl electrophiles
[1]
and silicon (pro)nucleophiles is a deceptively simple-looking yet almost unprecedented reaction. Solutions to this challenge have only been disclosed recently by Fu and co-workers[2] as well as ourselves[3] (Scheme 1, left).[4] The successful catalytic systems differ in catalyst and silicon source but share the features of a radical process. Our contribution included an indepth analysis of the reaction mechanism, and its radical nature prompted us to look for redox-active alkyl electrophiles other than iodides and bromides that would engage in a redox reaction with the silicon-based copper intermediate. Readily accessible aliphatic esters derived from N-hydroxyphthalimide (NHPI) fall into this category. These were discovered by Okada and co-workers and are a light-stable alternative to Barton esters.[5] Single-electron-transfer reduction initiates decarboxylation to generate an alkyl radical.[6] Application of this reaction mode in photocatalysis[7, 8] and transition-metal catalysis[9, 10] has led to the development of numerous procedures for carbon–carbon bond formation. We report here the use of NHPI esters for the formation of carbon–silicon bonds[11] on the basis of our previously established copper catalysis[3] with Si@B reagents[12, 13] as silicon pronucleophiles (Scheme 1, gray box). The new method enables C(sp3)@Si cross-coupling through decarboxylative silylation of aliphatic carboxylic acid derivatives (Scheme 1, right).[14]
[*] W. Xue, Prof. Dr. M. Oestreich Institut ffr Chemie, Technische Universit-t Berlin Strasse des 17. Juni 115, 10623 Berlin (Germany) E-mail: [email protected] Homepage: http://www.organometallics.tu-berlin.de Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.1002/anie.201706611. Angew. Chem. Int. Ed. 2017, 56, 11649 –11652
Scheme 1. Existing and planned methods for the cross-coupling of unactivated alkyl electrophiles and silicon (pro)nucleophiles. R1, R2, and R3 = Alkyl and H, R = Alkyl and/or Aryl. dtbpy = 4,4’-di-tert-butyl2,2’-bipyridine, diglyme = 1-methoxy-2-(2-methoxyethoxy)ethane, DMA = N,N-dimethylacetamide, DMF = N,N-dimethylformamide, NHPI = N-hydroxyphthalimide, pin = pinacolato.
After substantial optimization (see the Supporting Information), excellent yield was obtained with copper(I) thiophene-2-carboxylate (CuTc) as the (pre)catalyst, together with dtbpy and Cy3P as ligands in THF/NMP (9:1) at room temperature (2 a!7 aa with 1 a, Table 1, entry 1). Control experiments showed that the copper salt, the ligands, and the base are necessary (entries 2–5). Notably, the combination of the bipyridine and the phosphine is crucial to secure high yield: Neither dtbpy nor Cy3P alone promoted the decarboxylative silylation in satisfactory yield (entries 3 and 4). An extensive screening of alkoxides did not give better results except for with LiOtBu (entries 6–9). Using the heteroatomsubstituted Si@B reagent Me2PhSiB(NiPr2)2[13c] instead of Me2PhSiBpin (1 a) was unsuccessful (entry 10), and the zincbased silicon nucleophile (Me2PhSi)2Zn[15] afforded mediocre yield (entry 11). We also tested an array of other potentially redox-active esters (3 a–6 a) but none led to the desired coupling in more than trace amounts (entries 12–15). Importantly, the reaction proceeded equally well in the dark (entry 16). With the catalytic system in hand, we explored the substrate scope of the decarboxylative silylation (Schemes 2 and 3). As summarized in Scheme 2, the new method displayed splendid functional-group tolerance. In addition to model substrate 2 a, other unfunctionalized cyclic (2 b), acyclic (2 c), and benzylic (2 d) secondary coupling partners also participated in the reaction. An internal alkene (2 e) and a Boc-protected amine (2 f) were accepted. LiOtBu was generally superior to NaOEt as the base in the coupling of primary NHPI esters. A wide range of functional groups was compatible, including a methyl phenyl ether (2 g), an ethyl ester (2 h), and carbonyl groups (as in the dehydrocholic acid skeleton 2 i). To our delight, the NHPI esters of 3-pyridine-
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Table 1: Selected examples from optimization of the reaction conditions.[a]
Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Ester 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 3a 4a 5a 6a 2a
Yield [%][b]
Variation none without CuTc without dtbpy without Cy3P without NaOEt LiOtBu instead of NaOEt NaOtBu instead of NaOEt KOtBu instead of NaOEt KOEt instead of NaOEt Me2PhSiB(NiPr2)2 instead of 1 a (Me2PhSi)2Zn instead of 1 a none none none none in dark
91 (86)[c] trace 25 46 6 86 42 8 48 trace 30 10 trace trace trace 90
[a] All reactions performed on a 0.20 mmol scale. [b] Determined by GLC analysis with tetracosane as an internal standard. [c] Yield of isolated product after purification by flash chromatography on silica gel. NMP = N-methyl-2-pyrrolidone, Tc = thiophene-2-carboxylate.
Scheme 2. Scope I: Copper-catalyzed decarboxylative silylation of aliphatic NHPI esters. [a] Formed along with minor amounts of styrene. [b] X-ray analysis. Boc = tert-butoxycarbonyl, Bn = benzyl.
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Scheme 3. Scope II: Copper-catalyzed decarboxylative silylation of NHPI esters derived from a-amino acids. [a] X-ray analysis. Cbz = benzyloxycarbonyl.
propionic acid (2 j) and phenylpropionic acid (2 k), which could undergo styrene formation by b-elimination, converted into the corresponding silanes in moderate yields. Moreover, the silyl group was successfully installed a to an oxygen atom (2 l!7 la). Likely for steric reasons, tertiary NHPI esters reacted only sluggishly (see the Supporting Information for details) but adamantyl-substituted 2 m furnished 7 ma in acceptable yield. Considering the relevance of the motif of a-silylated amines for peptide isosteres,[16, 17] we set out to extend our decarboxylative silylation to their synthesis starting from ubiquitous a-amino acids (Scheme 3). We began with the Boc-protected (S)-proline derivative 2 n employing the different Si@B reagents 1 a–c. With phenyl-substituted 1 a and 1 b,[13a] 7 na and 7 nb formed in 70 % and 43 % yield, respectively, while the less reactive, purely alkyl-substituted 1 c[13b] failed to give 7 nc. Likewise, the non-canonical 2 o, (S)phenylalanine-derived 2 p, and (S)-tryptophan-derived 2 q yielded the a-silylated amines 7 oa–qa in moderate isolated yields. No substrate control was seen in the decarboxylative silylation of isoleucine derivative 2 r, which afforded 7 ra in 46 % yield with a 50:50 diastereomeric ratio. When phthalyl and Cbz instead of Boc were chosen as the electron-withdrawing protecting group on racemic alanine (2 s) and (S)proline (2 t), similar outcomes were obtained. Also, diethylprotected racemic valine derivative 2 u transformed into 7 ua in good yield, thus demonstrating the possibility of accessing a series of dialkyl-protected a-silylated amines with our method. In analogy to our copper-catalyzed dehalogenative silylation (Scheme 1, left),[3a] we assumed that the present decarboxylative silylation would also proceed through radical intermediates. To test for this, precursor 2 v was prepared and subjected to the standard conditions (Scheme 4, top); ringopened 8 va was isolated in moderate yield without the
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Scheme 5. Proposed catalytic cycle for the decarboxylative silylation.
Scheme 4. Control experiments to verify the radical mechanism.
formation of cyclopropyl-containing 7 va. Similarly, 2 w as a possible precursor for hex-5-enyl radical cyclization underwent the competing 5-exo-trig ring closure to 9 wa in 21 % yield along with linear 7 wa (Scheme 4, top). A racemization experiment with enantioenriched (S)-2 n proceeded with complete loss of the stereochemical information at the a carbon atom (Scheme 4, middle); as expected, the same result was obtained with (R)-2 n. Moreover, 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) inhibited our model reaction, and the cyclohexyl/TEMPO adduct was detected in small quantities (2 a!7 aa along with 10 a, Scheme 4, bottom). When 4-methylstyrene (11) was used to trap the cyclohexyl radical, C(sp3)@C(sp3) bond formation occurred in 17 % yield at the expense of C(sp3)@Si bond formation (2 a!7 aa along with 12 a, Scheme 4, bottom). These findings, together with convincing literature precedence that NHPI esters function as alkyl-radical surrogates in photocatalysis[7, 8] and nickel chemistry,[9] strongly support the involvement of radicals in this copper-catalyzed decarboxylative silylation. On the basis of the above results and our previous work,[3a] we suggest a radical catalytic cycle for this copper-catalyzed C(sp3)@Si cross-coupling (Scheme 5). The cationic copper(I) complex 13+ captures the silicon nucleophile (see quantumchemical calculations in Ref. [3a] for base-mediated release Angew. Chem. Int. Ed. 2017, 56, 11649 –11652
from the Si@B pronucleophile) to form the silicon-based copper(I) complex 14 a. After single-electron transfer (SET) from 14 a to the electron-accepting NHPI ester 2 a, the radical cation 15 aC+ is formed along with the radical anion 16 aC@ . The latter is further decarboxylated to afford the cyclohexyl radical (CyC). Radical recombination of 15 aC+ and CyC will ultimately deliver the cross-coupled 7 aa and regenerate copper(I) catalyst 13+. In summary, we disclose herein a copper-catalyzed decarboxylative cross-coupling of NHPI esters and Si@B reagents to build C(sp3)@Si bonds. It is the first example of NHPI esters being used as coupling partners in copper catalysis. The application of this method to a-amino acidderived NHPI esters is particularly noteworthy. The substrate scope generally compares well with existing methods, for example, decarboxylative borylation for C(sp3)@B bond formation.[14] This new C(sp3)@Si cross-coupling is a useful addition to the recently reported dehalogenative processes.[2, 3a]
Acknowledgements W.X. thanks the China Scholarship Council (CSC) for a predoctoral fellowship (2015–2019). M.O. is indebted to the Einstein Foundation (Berlin) for an endowed professorship. We thank Dr. Elisabeth Irran (TU Berlin) for the X-ray analyses.
Conflict of interest The authors declare no conflict of interest. Keywords: copper · cross-coupling · decarboxylation · radical reactions · silicon How to cite: Angew. Chem. Int. Ed. 2017, 56, 11649 – 11652 Angew. Chem. 2017, 129, 11808 – 11811
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Communications [1] State-of-the-art reviews of cross-coupling reactions of alkyl electrophiles: a) G. C. Fu, ACS Cent. Sci. 2017, 3, 692 – 700; b) A. Kaga, S. Chiba, ACS Catal. 2017, 7, 4697 – 4706; c) G. C. Fu, Science 2016, 354, 1265 – 1269; d) J. Gu, X. Wang, W. Xue, H. Gong, Org. Chem. Front. 2015, 2, 1411 – 1421; e) D. J. Weix, Acc. Chem. Res. 2015, 48, 1767 – 1775. [2] C. K. Chu, Y. Liang, G. C. Fu, J. Am. Chem. Soc. 2016, 138, 6404 – 6407. [3] a) W. Xue, Z.-W. Qu, S. Grimme, M. Oestreich, J. Am. Chem. Soc. 2016, 138, 14222 – 14225; b) J. Scharfbier, M. Oestreich, Synlett 2016, 27, 1274 – 1276. [4] The opposite approach, i.e., the cross-coupling of alkyl nucleophiles and silicon electrophiles: A. P. Cinderella, B. Vulovic, D. A. Watson, J. Am. Chem. Soc. 2017, 139, 7741 – 7744. [5] a) K. Okada, K. Okamoto, N. Morita, K. Okubo, M. Oda, J. Am. Chem. Soc. 1991, 113, 9401 – 9402; b) K. Okada, K. Okubo, N. Morita, M. Oda, Tetrahedron Lett. 1992, 33, 7377 – 7380; c) K. Okada, K. Okubo, N. Morita, M. Oda, Chem. Lett. 1993, 22, 2021 – 2024. [6] Recent reviews: a) T. Patra, D. Maiti, Chem. Eur. J. 2017, 23, 7382 – 7401; b) S. Roslin, L. R. Odell, Eur. J. Org. Chem. 2017, 1993 – 2007; c) Ref. [1b]. [7] a) C. R. Jamison, L. E. Overman, Acc. Chem. Res. 2016, 49, 1578 – 1586 (account); b) G. Pratsch, G. L. Lackner, L. E. Overman, J. Org. Chem. 2015, 80, 6025 – 6036. [8] a) Y. Jin, H. Fu, Asian J. Org. Chem. 2017, 6, 368 – 385 (focus review); b) C. Gao, J. Li, J. Yu, H. Yang, H. Fu, Chem. Commun. 2016, 52, 7292 – 7294; c) Y. Jin, H. Yang, H. Fu, Chem. Commun. 2016, 52, 12909 – 12912. [9] Nickel catalysis: a) J. Cornella, J. T. Edwards, T. Qin, S. Kawamura, J. Wang, C.-M. Pan, R. Gianatassio, M. Schmidt, M. D. Eastgate, P. S. Baran, J. Am. Chem. Soc. 2016, 138, 2174 – 2177; b) K. M. M. Huihui, J. A. Caputo, Z. Melchor, A. M. Olivares, A. M. Spiewak, K. A. Johnson, T. A. DiBenedetto, S. Kim, L. K. G. Ackerman, D. J. Weix, J. Am. Chem. Soc. 2016, 138, 5016 – 5019; c) T. Qin, J. Cornella, C. Li, L. R. Malins, J. T. Edwards, S. Kawamura, B. D. Maxwell, M. D. Eastgate, P. S. Baran, Science 2016, 352, 801 – 805; d) J. Wang, T. Qin, T.-G. Chen, L. Wimmer, J. T. Edwards, J. Cornella, B. Vokits, S. A. Shaw, P. S. Baran, Angew. Chem. Int. Ed. 2016, 55, 9676 – 9679; Angew. Chem. 2016, 128, 9828 – 9831; e) J. T. Edwards, R. R. Merchant, K. S. McClymont, K. W. Knouse, T. Qin, L. R. Malins, B. Vokits, S. A. Shaw, D.-H. Bao, F.-L. We, T. Zhou, M. D. Eastgate, P. S. Baran, Nature 2017, 545, 213 – 218.
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[10] Iron catalysis: F. Toriyama, J. Cornella, L. Wimmer, T.-G. Chen, D. D. Dixon, G. Creech, P. S. Baran, J. Am. Chem. Soc. 2016, 138, 11132 – 11135. [11] Examples of C(sp2)@Si bond formation involving decarbonylation: a) L. Guo, A. Chatupheeraphat, M. Rueping, Angew. Chem. Int. Ed. 2016, 55, 11810 – 11813; Angew. Chem. 2016, 128, 11989 – 11992; b) X. Pu, J. Hu, Y. Zhao, Z. Shi, ACS Catal. 2016, 6, 6692 – 6698; an example of C(sp)@Si bond formation: c) L. Zhang, Z. Hang, Z.-Q. Liu, Angew. Chem. Int. Ed. 2016, 55, 236 – 239; Angew. Chem. 2016, 128, 244 – 247. [12] Recent reviews of Si@B chemistry: a) L. B. Delvos, M. Oestreich in Science of Synthesis Knowledge Updates 2017/1 (Ed.: M. Oestreich), Thieme, Stuttgart, 2017, pp. 65 – 176; b) M. Oestreich, E. Hartmann, M. Mewald, Chem. Rev. 2013, 113, 402 – 441. [13] The preparation of Si@B reagents: a) M. Suginome, T. Matsuda, Y. Ito, Organometallics 2000, 19, 4647 – 4649 [Me2PhSiBpin (1 a) and MePh2SiBpin (1 b)]; b) T. A. Boebel, J. F. Hartwig, Organometallics 2008, 27, 6013 – 6019 [Et3SiBpin (1 c)]; c) M. Suginome, T. Fukuda, H. Nakamura, Y. Ito, Organometallics 2000, 19, 719 – 721 [(Me2PhSiB(NiPr2)2]. [14] Recent examples of decarboxylative borylation using NHPI esters: a) C. Li, J. Wang, L. M. Barton, S. Yu, M. Tian, D. S. Peters, M. Kumar, A. W. Yu, K. A. Johnson, A. K. Chatterjee, M. Yan, P. S. Baran, Science DOI: https://doi.org/10.1126/ science.aam7355; b) D. Hu, L. Wang, P. Li, Org. Lett. 2017, 19, 2770 – 2773; c) L. Candish, M. Teders, F. Glorius, J. Am. Chem. Soc. 2017, 139, 7440 – 7443; d) A. Fawcett, J. Pradeilles, Y. Wang, T. Mutsuga, E. L. Myers, V. K. Aggarwal, Science 2017, 357, 283 – 286. [15] A. Weickgenannt, M. Oestreich, Chem. Eur. J. 2010, 16, 402 – 412. [16] Reviews: a) G. K. Min, D. Hern#ndez, T. Skrydstrup, Acc. Chem. Res. 2013, 46, 457 – 470; b) S. M. Sieburth, C.-A. Chen, Eur. J. Org. Chem. 2006, 311 – 322. [17] a) D. J. Vyas, R. Frçhlich, M. Oestreich, Org. Lett. 2011, 13, 2094 – 2097; b) A. Hensel, K. Nagura, L. B. Delvos, M. Oestreich, Angew. Chem. Int. Ed. 2014, 53, 4964 – 4967; Angew. Chem. 2014, 126, 5064 – 5067; c) T. Mita, M. Sugawara, K. Saito, Y. Sato, Org. Lett. 2014, 16, 3028 – 3031; d) C. Zhao, C. Jiang, J. Wang, C. Wu, Q.-W. Zhang, W. He, Asian J. Org. Chem. 2014, 3, 851 – 855. Manuscript received: June 29, 2017 Accepted manuscript online: January 0, 0000 Version of record online: August 10, 2017
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International Edition: DOI: 10.1002/anie.201706611 German Edition: DOI: 10.1002/ange.201706611
Cross-Coupling
Copper-Catalyzed Decarboxylative Radical Silylation of Redox-Active Aliphatic Carboxylic Acid Derivatives Weichao Xue and Martin Oestreich* Abstract: A decarboxylative silylation of aliphatic N-hydroxyphthalimide (NHPI) esters using Si@B reagents as silicon pronucleophiles is reported. This C(sp3)@Si cross-coupling is catalyzed by copper(I) and follows a radical mechanism, even with exclusion of light. Both primary and secondary alkyl groups couple effectively, whereas tertiary alkyl groups are probably too sterically hindered. The functional-group tolerance is generally excellent, and a-heteroatom-substituted substrates also participate well. This enables, for example, the synthesis of a-silylated amines starting from NHPI esters derived from a-amino acids. The new method extends the still limited number of C(sp3)@Si cross-couplings of unactivated alkyl electrophiles.
The cross-coupling of unactivated alkyl electrophiles
[1]
and silicon (pro)nucleophiles is a deceptively simple-looking yet almost unprecedented reaction. Solutions to this challenge have only been disclosed recently by Fu and co-workers[2] as well as ourselves[3] (Scheme 1, left).[4] The successful catalytic systems differ in catalyst and silicon source but share the features of a radical process. Our contribution included an indepth analysis of the reaction mechanism, and its radical nature prompted us to look for redox-active alkyl electrophiles other than iodides and bromides that would engage in a redox reaction with the silicon-based copper intermediate. Readily accessible aliphatic esters derived from N-hydroxyphthalimide (NHPI) fall into this category. These were discovered by Okada and co-workers and are a light-stable alternative to Barton esters.[5] Single-electron-transfer reduction initiates decarboxylation to generate an alkyl radical.[6] Application of this reaction mode in photocatalysis[7, 8] and transition-metal catalysis[9, 10] has led to the development of numerous procedures for carbon–carbon bond formation. We report here the use of NHPI esters for the formation of carbon–silicon bonds[11] on the basis of our previously established copper catalysis[3] with Si@B reagents[12, 13] as silicon pronucleophiles (Scheme 1, gray box). The new method enables C(sp3)@Si cross-coupling through decarboxylative silylation of aliphatic carboxylic acid derivatives (Scheme 1, right).[14]
[*] W. Xue, Prof. Dr. M. Oestreich Institut ffr Chemie, Technische Universit-t Berlin Strasse des 17. Juni 115, 10623 Berlin (Germany) E-mail: [email protected] Homepage: http://www.organometallics.tu-berlin.de Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.1002/anie.201706611. Angew. Chem. Int. Ed. 2017, 56, 11649 –11652
Scheme 1. Existing and planned methods for the cross-coupling of unactivated alkyl electrophiles and silicon (pro)nucleophiles. R1, R2, and R3 = Alkyl and H, R = Alkyl and/or Aryl. dtbpy = 4,4’-di-tert-butyl2,2’-bipyridine, diglyme = 1-methoxy-2-(2-methoxyethoxy)ethane, DMA = N,N-dimethylacetamide, DMF = N,N-dimethylformamide, NHPI = N-hydroxyphthalimide, pin = pinacolato.
After substantial optimization (see the Supporting Information), excellent yield was obtained with copper(I) thiophene-2-carboxylate (CuTc) as the (pre)catalyst, together with dtbpy and Cy3P as ligands in THF/NMP (9:1) at room temperature (2 a!7 aa with 1 a, Table 1, entry 1). Control experiments showed that the copper salt, the ligands, and the base are necessary (entries 2–5). Notably, the combination of the bipyridine and the phosphine is crucial to secure high yield: Neither dtbpy nor Cy3P alone promoted the decarboxylative silylation in satisfactory yield (entries 3 and 4). An extensive screening of alkoxides did not give better results except for with LiOtBu (entries 6–9). Using the heteroatomsubstituted Si@B reagent Me2PhSiB(NiPr2)2[13c] instead of Me2PhSiBpin (1 a) was unsuccessful (entry 10), and the zincbased silicon nucleophile (Me2PhSi)2Zn[15] afforded mediocre yield (entry 11). We also tested an array of other potentially redox-active esters (3 a–6 a) but none led to the desired coupling in more than trace amounts (entries 12–15). Importantly, the reaction proceeded equally well in the dark (entry 16). With the catalytic system in hand, we explored the substrate scope of the decarboxylative silylation (Schemes 2 and 3). As summarized in Scheme 2, the new method displayed splendid functional-group tolerance. In addition to model substrate 2 a, other unfunctionalized cyclic (2 b), acyclic (2 c), and benzylic (2 d) secondary coupling partners also participated in the reaction. An internal alkene (2 e) and a Boc-protected amine (2 f) were accepted. LiOtBu was generally superior to NaOEt as the base in the coupling of primary NHPI esters. A wide range of functional groups was compatible, including a methyl phenyl ether (2 g), an ethyl ester (2 h), and carbonyl groups (as in the dehydrocholic acid skeleton 2 i). To our delight, the NHPI esters of 3-pyridine-
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Table 1: Selected examples from optimization of the reaction conditions.[a]
Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Ester 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 3a 4a 5a 6a 2a
Yield [%][b]
Variation none without CuTc without dtbpy without Cy3P without NaOEt LiOtBu instead of NaOEt NaOtBu instead of NaOEt KOtBu instead of NaOEt KOEt instead of NaOEt Me2PhSiB(NiPr2)2 instead of 1 a (Me2PhSi)2Zn instead of 1 a none none none none in dark
91 (86)[c] trace 25 46 6 86 42 8 48 trace 30 10 trace trace trace 90
[a] All reactions performed on a 0.20 mmol scale. [b] Determined by GLC analysis with tetracosane as an internal standard. [c] Yield of isolated product after purification by flash chromatography on silica gel. NMP = N-methyl-2-pyrrolidone, Tc = thiophene-2-carboxylate.
Scheme 2. Scope I: Copper-catalyzed decarboxylative silylation of aliphatic NHPI esters. [a] Formed along with minor amounts of styrene. [b] X-ray analysis. Boc = tert-butoxycarbonyl, Bn = benzyl.
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Scheme 3. Scope II: Copper-catalyzed decarboxylative silylation of NHPI esters derived from a-amino acids. [a] X-ray analysis. Cbz = benzyloxycarbonyl.
propionic acid (2 j) and phenylpropionic acid (2 k), which could undergo styrene formation by b-elimination, converted into the corresponding silanes in moderate yields. Moreover, the silyl group was successfully installed a to an oxygen atom (2 l!7 la). Likely for steric reasons, tertiary NHPI esters reacted only sluggishly (see the Supporting Information for details) but adamantyl-substituted 2 m furnished 7 ma in acceptable yield. Considering the relevance of the motif of a-silylated amines for peptide isosteres,[16, 17] we set out to extend our decarboxylative silylation to their synthesis starting from ubiquitous a-amino acids (Scheme 3). We began with the Boc-protected (S)-proline derivative 2 n employing the different Si@B reagents 1 a–c. With phenyl-substituted 1 a and 1 b,[13a] 7 na and 7 nb formed in 70 % and 43 % yield, respectively, while the less reactive, purely alkyl-substituted 1 c[13b] failed to give 7 nc. Likewise, the non-canonical 2 o, (S)phenylalanine-derived 2 p, and (S)-tryptophan-derived 2 q yielded the a-silylated amines 7 oa–qa in moderate isolated yields. No substrate control was seen in the decarboxylative silylation of isoleucine derivative 2 r, which afforded 7 ra in 46 % yield with a 50:50 diastereomeric ratio. When phthalyl and Cbz instead of Boc were chosen as the electron-withdrawing protecting group on racemic alanine (2 s) and (S)proline (2 t), similar outcomes were obtained. Also, diethylprotected racemic valine derivative 2 u transformed into 7 ua in good yield, thus demonstrating the possibility of accessing a series of dialkyl-protected a-silylated amines with our method. In analogy to our copper-catalyzed dehalogenative silylation (Scheme 1, left),[3a] we assumed that the present decarboxylative silylation would also proceed through radical intermediates. To test for this, precursor 2 v was prepared and subjected to the standard conditions (Scheme 4, top); ringopened 8 va was isolated in moderate yield without the
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Scheme 5. Proposed catalytic cycle for the decarboxylative silylation.
Scheme 4. Control experiments to verify the radical mechanism.
formation of cyclopropyl-containing 7 va. Similarly, 2 w as a possible precursor for hex-5-enyl radical cyclization underwent the competing 5-exo-trig ring closure to 9 wa in 21 % yield along with linear 7 wa (Scheme 4, top). A racemization experiment with enantioenriched (S)-2 n proceeded with complete loss of the stereochemical information at the a carbon atom (Scheme 4, middle); as expected, the same result was obtained with (R)-2 n. Moreover, 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) inhibited our model reaction, and the cyclohexyl/TEMPO adduct was detected in small quantities (2 a!7 aa along with 10 a, Scheme 4, bottom). When 4-methylstyrene (11) was used to trap the cyclohexyl radical, C(sp3)@C(sp3) bond formation occurred in 17 % yield at the expense of C(sp3)@Si bond formation (2 a!7 aa along with 12 a, Scheme 4, bottom). These findings, together with convincing literature precedence that NHPI esters function as alkyl-radical surrogates in photocatalysis[7, 8] and nickel chemistry,[9] strongly support the involvement of radicals in this copper-catalyzed decarboxylative silylation. On the basis of the above results and our previous work,[3a] we suggest a radical catalytic cycle for this copper-catalyzed C(sp3)@Si cross-coupling (Scheme 5). The cationic copper(I) complex 13+ captures the silicon nucleophile (see quantumchemical calculations in Ref. [3a] for base-mediated release Angew. Chem. Int. Ed. 2017, 56, 11649 –11652
from the Si@B pronucleophile) to form the silicon-based copper(I) complex 14 a. After single-electron transfer (SET) from 14 a to the electron-accepting NHPI ester 2 a, the radical cation 15 aC+ is formed along with the radical anion 16 aC@ . The latter is further decarboxylated to afford the cyclohexyl radical (CyC). Radical recombination of 15 aC+ and CyC will ultimately deliver the cross-coupled 7 aa and regenerate copper(I) catalyst 13+. In summary, we disclose herein a copper-catalyzed decarboxylative cross-coupling of NHPI esters and Si@B reagents to build C(sp3)@Si bonds. It is the first example of NHPI esters being used as coupling partners in copper catalysis. The application of this method to a-amino acidderived NHPI esters is particularly noteworthy. The substrate scope generally compares well with existing methods, for example, decarboxylative borylation for C(sp3)@B bond formation.[14] This new C(sp3)@Si cross-coupling is a useful addition to the recently reported dehalogenative processes.[2, 3a]
Acknowledgements W.X. thanks the China Scholarship Council (CSC) for a predoctoral fellowship (2015–2019). M.O. is indebted to the Einstein Foundation (Berlin) for an endowed professorship. We thank Dr. Elisabeth Irran (TU Berlin) for the X-ray analyses.
Conflict of interest The authors declare no conflict of interest. Keywords: copper · cross-coupling · decarboxylation · radical reactions · silicon How to cite: Angew. Chem. Int. Ed. 2017, 56, 11649 – 11652 Angew. Chem. 2017, 129, 11808 – 11811
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