DOI: 10.1002/chem.201405102
Communication
& Synthetic Methods
Copper-Mediated/Catalyzed Oxyalkylation of Alkenes with Alkylnitriles Ala Bunescu, Qian Wang, and Jieping Zhu*[a] Abstract: A copper-promoted oxyalkylation of alkenes with alkylnitriles has been developed. The protocol provides rapid access to phthalides (g-lactones) or isochromanones (d-lactones) via the formation of a C(sp3) C(sp3) and a C(sp3) O bond with the generation of up to two quaternary carbon atoms. Mechanistic studies suggest that this reaction is initiated by the formation of the C(sp3) C(sp3) bond rather than the C(sp3) O bond. Catalytic conditions were subsequently developed using carboxylic acid as an internal nucleophile.
The difunctionalization of alkenes represents a domain of major interest in organic synthesis due to the availability of the starting materials and the possibility to attain molecular complexity and diversity in one single step. Among the available methods, metal-catalyzed transformations have emerged as a powerful tool for this purpose.[1] However, C(sp3) C(sp3) bond formation remains challenging, mainly due to the competitive b-hydride elimination process.[2] In recent years, copper has gained much popularity as a catalyst for two important processes: the C(sp3) C(sp3) cross-dehydrogenative coupling (CDC)[3] and the difunctionalization of alkenes.[4–6] Regardless of remarkable achievements realized in the field, examples of copper-mediated/catalyzed difunctionalization of alkenes with generation of a C(sp3) C(sp3) bond remain rare.[7, 8] The formation of organometallic complexes (Ln, Rh, Fe, Ru) by activating a-C H bond of acetonitrile has been documented in the past.[9] Nevertheless, the use of nitrile with synthetic purpose is limited mainly to its enolate form[10, 11] requiring a strong base [pKa (MeCN) 31.3, DMSO] for its formation or the use of activated nitriles like b-cyanocarbonyls (pKa 13–14, DMSO) or a-arylacetonitriles (pKa 21.9, DMSO). Recently, Liu and co-workers reported an elegant Pd-catalyzed oxidative arylalkylation of alkenes involving an a-CH activation of acetonitrile using PhI(OCOtBu)2 (1.1 equiv) and AgF (4.0 equiv) as copromoters [Scheme 1, Eq. (1)].[2a] As a continuation of our ongoing project dealing with the metal-catalyzed C(sp3) H func[a] A. Bunescu, Dr. Q. Wang, Prof. Dr. J. Zhu Laboratory of Synthesis and Natural Product Institute of Chemical Sciences and Engineering Ecole Polytechnique Fdrale de Lausanne EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201405102. Chem. Eur. J. 2014, 20, 14633 – 14636
Scheme 1. Functionalization of alkenes with alkylnitriles.
tionalization,[12, 13] we report herein a copper mediated/catalyzed oxyalkylation of alkenes using alkylnitriles as reaction partners leading to functionalized phthalides and isochromanones [Scheme 1, Eq. (2)]. Phthalides are widely present in natural products[14] and pharmaceuticals,[15] and have proved useful as building blocks in organic synthesis.[16] Using N-(tert-butyl)-2-(prop-1-en-2-yl)benzamide (1 a, X = NHtBu) and acetonitrile as test substrates, conditions were surveyed by varying the copper salts, the oxidants, the ligands, the bases,[17] and the temperature. The initial conditions, which led to reasonable yield of 2 a, were as follows: Cu(OTf)2 (2.0 equiv), 1,10-phenanthroline (1.0 equiv), K3PO4 (2.0 equiv) and di-tert-butylperoxide (DTBP; 2.0 equiv) at 140 8C (for details, see the Supporting Information). Under these conditions, two oxyalkylation products, at the expense of isoindolinone resulting from the aminoalkylation process, were formed in 58 % yield (by NMR spectroscopy; 2 a/2 b = 1:1; Table 1, entry 1). Gratifyingly, by adding water (11.0 equiv) into the reaction mixture, the yield of oxyalkylation products increased with an improved ratio of 2 a to 2 b (isolated in 65 % yield; 2 a/2 b = 1.5:1; Table 1, entry 2). Further fine-tuning of the reaction conditions indicated that 2,2’-bipyridine was the ligand of choice (Table 1, entries 4–7). In these preliminary experiments, we also isolated nitrile 3, which could have important mechanistic implications (see below). Finally, the nature of the amide group (X = NHtBu, NHMe, or NMe2) impacted significantly the product yield (Table 1, entries 7–9). Using N,N-dimethylamide 1 c (X = NMe2) as starting material, phthalide 2 a was isolated as a sole product in 86 % yield (Table 1, entry 10). The yield of 2 a decreased significantly when Cu/ligand ratio was reduced to 1:1 (Table 1, entry 10).
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Communication Table 1. Oxyalkylation of alkenes: survey of reaction conditions.
Entry
X
Ligand
Base/Additive
Yield of 2 a [%][b]
1 2 3 4 5 6 7 8 9 10
NHtBu NHtBu NHtBu NHtBu NHtBu NHtBu NHtBu NHMe NMe2 NMe2
1,10-phen 1,10-phen 1,10-phen 1,10-phen pyridine bpym 2,2’-bipy 2,2’-bipy 2,2’-bipy 2,2’-bipy
K3PO4 K3PO4/water water KH2PO4/water K3PO4/water K3PO4/water K3PO4/water K3PO4/water K3PO4/water K3PO4/water
(58)[c] 65 (72)[c] degradation degradation (21) (38) 67 75 86 (31)[d]
[a] Reactions were carried out on 0.05 mmol scale in sealed tubes. Standard conditions: Cu(OTf)2 (2.0 equiv), Ligand (1.0 equiv), DTBP (2.0 equiv), Base (2.0 equiv), H2O (11.0 equiv), air, 140 8C, CH3CN (0.1 m). [b] Yield in parentheses is calculated based on 1H NMR spectra using CH2Br2 as an internal standard. [c] Mixture of 2 a and 2 b. [d] Ligand (2.0 equiv) was used. 1,10-phen = 1,10-phenanthroline; bpym = 2,2’-bipyrimidine; 2,2’-bipy = 2,2’-bipyridine; DTBP = di-tert-butyl peroxide.
The scope of the oxyalkylation of alkenes was next investigated using tethered N,N-dimethyl amide as an internal nucleophile (Scheme 2). The presence of an electron-withdrawing (F) or -donating group (Me, OMe, -OCH2O-) at different positions of aromatic ring (ring A) was tolerated (2 c–2 g). The reaction tolerated well the substituent at the b-position of the double bond (R2 = Me, Et, Ph), with the phenyl substituent leadng to an improvement in yield (2 i, 92 %). When a mixture of trisubstituted (Z)/(E)-2-(but-2-en-2-yl)-N,N-dimethylbenzamide (R2 = R3 = Me; Z/E = 4/1) was used, the desired phthalide 2 j was isolated in 55 % yield as a mixture of two diastereomers together with unreacted E isomer.[18] Gratifyingly, other alkyl nitrile, such as propionitrile, n-butyronitrile, n-valeronitrile and 3methoxypropionitrile, participated in this reaction to give the desired functionalized heterocycles in yields ranging from 66 % to 77 % (2 k–2 o; Scheme 2). More importantly, the reaction with isobutyronitrile resulted in the formation of phthalide 2 p in 65 % yield with concurrent generation of two quaternary carbon atoms. To our knowledge, this represented the first example wherein an a-substituted alkylnitrile participated in the metal-promoted addition reaction to alkenes. Interestingly, benzyl cyanide failed to participate in the oxyalkylation reaction with 1 c. When N,N-dimethyl-4-phenylpent-4-enamide was used as substrate, the desired g-lactone 2 q was obtained in 61 % yield (isolated product). Formation of g-lactone was also possible, as exemplified by the synthesis of isochromanone 2 r (69 %). The reaction of 1 c (X = NMe2) with MeCN was completely inhibited in the presence of a radical scavenger (TEMPO), with 2[(2,2,6,6-tetramethylpiperidin-1-yl)oxy]acetonitrile 4 being the only isolable product at the expense of alkoxyamine 5[5] (Scheme 3). This result, together with the isolation of alkene 3 in our initial experiments (Table 1), indicated that the domino Chem. Eur. J. 2014, 20, 14633 – 14636
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Scheme 2. Scope of oxyalkylation reaction: [a] Reactions were carried out on 0.1 mmol scale in sealed tubes. Conditions: Cu(OTf)2 (2.0 equiv), bipy (1.0 equiv), DTBP (2.0 equiv), K3PO4 (2.0 equiv), H2O (11.0 equiv), 140 8C. [b] Yield based on conversion.
Scheme 3. Radical trapping experiments. [a] Yield of isolated product. [b] Yield by NMR spectroscopy.
oxyalkylation of 1 c leading to phthalides 2 was initiated by the formation of the C C bond rather than the C O bond.[5] Performing the radical trapping experiment in the absence of Cu(OTf)2 or K3PO4 failed to produce compound 4 (Scheme 3, exp. 2 and 3). The presence of both salts was therefore essential to the activation of acetonitrile. In contrast, compound 4 was formed in 51 % yield (by NMR) in the absence of DTBP indicating that DTBP was not essential for acetonitrile activation (Scheme 3, exp. 4). Indeed, the oxyalkylation proceeded in the absence of DTBP under otherwise identical conditions, although the reaction stopped at 40 % conversion even in the presence of two equivalents of Cu(OTf)2. In addition, 4 was generated in a similar yield when the last control experiment
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Communication was repeated under a strictly inert atmosphere (Scheme 3, exp. 5).[19] Taking into consideration the above results, possible reaction pathways leading to phthalide 2 are depicted in Scheme 4. Co-
that the oxyalkylation of 1 d could indeed take place under catalytic conditions (see the Supporting Information for details of the optimization of reaction conditions). Under optimum conditions [Cu(OAc)2 (0.3 equiv), 1,10-phen (0.3 equiv), Na3PO4 (2.0 equiv), DTBP (2.0 equiv), 140 8C, N2, 3 h], reaction of 1 d and MeCN afforded 2 a in 77 % yield. The catalytic conditions turned out to be quite general (Scheme 5). The reaction was
Scheme 4. Possible reaction pathways.
ordination of copper(II) triflate to nitrile followed by deprotonation of the complex A by potassium phosphate would produce the organocopper species B[20] that, after homolytic cleavage of the C CuII bond, would deliver the cyanomethyl radical C. Radical addition to alkene 1 c would produce the benzylic radical D. Intermediate D could be further oxidized to a cationic intermediate E,[21] which upon cyclization afforded F. Formation of an organocopper(III) intermediate G from D followed by reductive elimination could also provide intermediate F. Alternatively, the reaction could also be initiated by carbocuppration of 1 c by B leading to H which could subsequently be oxidized to intermediate G. Finally, hydrolysis of the carboximidate salt F furnished phthalide 2 a. Oxidation of CuI with DTBP would regenerate the CuII salt.[7c, 22–24] To gain insight on whether the reaction was initiated by carbocupration or by radical addition process, the following control experiments were performed. Both 2-cyclopropylacetonitrile (6) and 2-(1-cyclopropylvinyl)-N,N-dimethylbenzamide (7), failed to participate in this reaction, whereas the reaction of 8 with acetonitrile under standard conditions afforded the lactone 2 s, albeit with a reduced yield (34 %).[25] Although the results of these cyclopropane radical clock experiments, together with the lack of diastereoselectivity in the formation of 2 j from its Z-olefinic precursor seemed in favor of a radical process (Scheme 4, pathway a), the alternative carbocupration process (Scheme 4, pathway b) cannot be discarded at the present stage of development. The reason why 2 equivalents of Cu(OTf)2 was needed to drive the reaction to completion is at present unclear. We hypothesized that the amide function of the starting material, as well as the in situ-generated dimethylamine might coordinate strongly to Cu leading to catalyst poisoning. With this rationale in mind, we investigated the reaction between 2-(prop-1-en-2yl)benzoic acid (1 d) and acetonitrile. We were pleased to find Chem. Eur. J. 2014, 20, 14633 – 14636
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Scheme 5. Oxyalkylation of alkenes with alkylnitriles under catalytic conditions. [a] Conditions: Cu(OAc)2 (0.3 equiv), 1,10-phen (0.3 equiv), Na3PO4 (2.0 equiv), DTBP (2.0 equiv in 2 portions), N2, 140 8C.
insensitive to the electronic properties of the aromatic ring and was operational with trisubstituted olefin leading to compound 2 j. Propionitrile and butyronitrile reacted with 1 d to produce the corresponding phthalides 2 k and 2 t, albeit with reduced yields relative to the stoichiometric process. The g-lactone can also be produced as evidenced by the synthesis of isochromanone 2 r (58 %). In summary, we developed a simple Cu-promoted/catalyzed oxyalkylation of alkenes with alkyl nitriles. This unprecedented reaction afforded an efficient access to 3,3-disubstituted phthalides and isochromanones through the formation of a C(sp3) C(sp3) and a C(sp3) O bond. The reaction displayed a wide application scope and up to two quaternary carbon atoms could be generated in this process. Preliminary mechanistic studies suggested that the formation of alkylcuprate intermediate by the dual action of copper salt and potassium phosphate is key to the present process. To our knowledge, this report represents the first examples of alkylative lactonization of alkenes by unactivated alkylnitriles.
Experimental Section Catalytic process: To a mixture of acid 1 (1.0 equiv), Cu(OAc)2 (0.3 equiv), 1,10-phen (0.3 equiv) and Na3PO4 (2.0 equiv) in RCN (0.1 m) was added DTBP (1.0 equiv) and the tube was sealed and stirred at 140 8C under N2 atmosphere for 90 min. The reaction mixture was cooled to room temperature, a second portion of DTBP
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Communication (1.0 equiv) was added, and the tube was sealed and stirred at 140 8C under N2 atmosphere for an additional 90 min. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford heterocycle 2.
[9]
Acknowledgements
[10]
Financial support from EPFL (Switzerland) and the Swiss National Science Foundation (SNSF) is gratefully acknowledged.
[11]
Keywords: alkenes oxyalkylation
[12]
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alkylation
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copper
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lactones
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[1] a) D. M. Schultz, J. P. Wolfe, Synthesis 2012, 3, 351 – 361; b) R. I. McDonald, G. Liu, S. S. Stahl, Chem. Rev. 2011, 111, 2981 – 3019; c) K. H. Jensen, M. S. Sigman, Org. Biomol. Chem. 2008, 6, 4083 – 4088; d) A. Minatti, K. Muniz, Chem. Soc. Rev. 2007, 36, 1142 – 1152; e) V. Kotov, C. C. Scarborough, S. S. Stahl, Inorg. Chem. 2007, 46, 1910 – 1923. [2] For Pd-catalyzed difunctionalization of alkenes with the formation of C(sp3) C(sp3) bonds, see: a) T. Wu, X. Mu, G. Liu, Angew. Chem. Int. Ed. 2011, 50, 12578 – 12581; Angew. Chem. 2011, 123, 12786 – 12789; b) K. B. Urkalan, M. S. Sigman, J. Am. Chem. Soc. 2009, 131, 180420 – 18043; for iron-catalyzed difunctionalization of alkene with the formation of C(sp3) C(sp3) see: c) W.-T. Wei, M.-B. Zhou, J.-H. Fan, W. Liu, R.-J. Song, Y. Liu, M. Hu, P. Xie, J.-H. Li, Angew. Chem. Int. Ed. 2013, 52, 3638 – 3641; Angew. Chem. 2013, 125, 3726 – 3729. [3] S. A. Girard, T. Knauber, C.-J. Li, Angew. Chem. Int. Ed. 2014, 53, 74 – 100; Angew. Chem. 2014, 126, 76 – 103. [4] S. R. Chemler, P. H. Fuller, Chem. Soc. Rev. 2007, 36, 1153 – 1160; b) A. E. Wendlandt, A. M. Suess, S. S. Stahl, Angew. Chem. Int. Ed. 2011, 50, 11062 – 11087; Angew. Chem. 2011, 123, 11256 – 11283; c) C. Zhang, C. Tang, N. Jiao, Chem. Soc. Rev. 2012, 41, 3464 – 3484. [5] For copper-catalyzed difunctionalization of olefins initiated by aminocupration, see: a) T. P. Zabawa, D. Kasi, S. R. Chemler, J. Am. Chem. Soc. 2005, 127, 11250 – 11251; b) W. Zeng, S. R. Chemler, J. Am. Chem. Soc. 2007, 129, 12948 – 12949; c) P. H. Fuller, J.-W. Kim, S. R. Chemler, J. Am. Chem. Soc. 2008, 130, 17638 – 17639; d) M. C. Paderes, S. R. Chemler, Eur. J. Org. Chem. 2011, 2011, 3679 – 3684; e) T. W. Liwosz, S. R. Chemler, J. Am. Chem. Soc. 2012, 134, 2020 – 2023; f) Y. Miller, L. Miao, A. S. Hosseini, S. R. Chemler, J. Am. Chem. Soc. 2012, 134, 12149 – 12156. [6] For examples of copper-catalyzed diamination of alkenes, see: a) B. Zhao, X. Peng, S. Cui, Y. Shi, J. Am. Chem. Soc. 2010, 132, 11009 – 11011; b) B. Zhao, X. Peng, Y. Zhu, T. A. Ramirez, R. G. Cornwall, Y. Shi, J. Am. Chem. Soc. 2011, 133, 20890 – 20900; c) Y.-F. Wang, X. Zhu, S. Chiba, J. Am. Chem. Soc. 2012, 134, 3679 – 3682; of alkynes: d) J. Li, L. Neuville, Org. Lett. 2013, 15, 1752 – 1755. [7] For copper catalyzed difunctionalization of alkenes with the formation of C(sp3) C(sp3) bonds, see: a) L. Huang, H. Jiang, C. Qi, X. Liu, J. Am. Chem. Soc. 2010, 132, 17652 – 17654; b) K.-K. Toh, Y.-F. Wang, E. P. J. Ng, S. Chiba, J. Am. Chem. Soc. 2011, 133, 13942 – 13945; c) Z. Li, Y. Zhang, L. Zhang, Z.-Q. Liu, Org. Lett. 2014, 16, 382 – 385. [8] For copper catalyzed trifluoromethylation of alkenes, see: a) A. T. Parsons, S. L. Buchwald, Angew. Chem. Int. Ed. 2011, 50, 9120 – 9123; Angew. Chem. 2011, 123, 9286 – 9289; b) J. Xu, Y. Fu, D.-F. Luo, Y.-Y. Jiang, B. Xiao, Z.-J. Liu, T.-J. Gong, L. Liu, J. Am. Chem. Soc. 2011, 133, 15300 – 15303; c) X. Wang, Y. Ye, S. Zhang, J. Feng, Y. Xu, Y. Zhang, J. Wang, J. Am. Chem. Soc. 2011, 133, 16410 – 16413; d) R. Zhu, R.; S. L. Buchwald, J. Am. Chem. Soc. 2012, 134, 12462 – 12465; S. L. Buchwald, J. Am. Chem. Soc. 2012, 134, 12462 – 12465; e) L. Chu, F.-L. Qing, Org. Lett. 2012, 14, 2106 – 2109; f) P. G. Janson, I. Ghoneim, N. O. Ilchenko, K. Szab, Org. Lett. 2012, 14, 2882 – 2885; g) R. Zhu, S. L. Buchwald, Angew. Chem. Int. Ed. 2013, 52, 12655 – 12658; Angew. Chem. 2013, 125, 12887 – 12890; h) H. Egami, R. Shimizu, S. Kawamura, M. Sodeoka, Angew. Chem. Chem. Eur. J. 2014, 20, 14633 – 14636
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Int. Ed. 2013, 52, 4000 – 4003; Angew. Chem. 2013, 125, 4092 – 4095; i) H. Egami, S. Kawamura, A. Miyazaki, M. Sodeoka, Angew. Chem. Int. Ed. 2013, 52, 7841 – 7844; Angew. Chem. 2013, 125, 7995 – 7998; j) For a highlight, see: A. Studer, Angew. Chem. Int. Ed. 2012, 51, 8950 – 8958; Angew. Chem. 2012, 124, 9082 – 9090. a) S. D. Ittel, C. A. Tolman, A. D. English, J. P. Jesson, J. Am. Chem. Soc. 1978, 100, 7577 – 7585; b) H. J. Heeres, A. Meetsma, J. H. Teuben, Angew. Chem. Int. Ed. 1990, 29, 420 – 422; Angew. Chem. 1990, 102, 449 – 450; c) D. Churchill, J. H. Shin, T. Hascall, J. M. Hahn, B. M. Bridgewater, G. Parkin, Organometallics 1999, 18, 2403 – 2406; d) M. E. Evans, T. Li, A. J. Vetter, R. D. Rieth, W. D. Jones, J. Org. Chem. 2009, 74, 6907 – 6914. a) D. A. Culkin, J. F. Hartwig, J. Am. Chem. Soc. 2002, 124, 9330 – 9331; b) J. You, J. G. Verkade, Angew. Chem. Int. Ed. 2003, 42, 5051 – 5053; Angew. Chem. 2003, 115, 5205 – 5207. For catalytic C H activation of nitriles, see: a) N. Kumagai, S. Matsunage, M. Shibasaki, J. Am. Chem. Soc. 2004, 126, 13632 – 13633; b) For a general review on metal enolate chemistry, see: F. Dns, A. Prez-Luna, F. Chemla, Chem. Rev. 2010, 110, 2366 – 2447. a) A. Salcedo, L. Neuville, J. Zhu, J. Org. Chem. 2008, 73, 3600 – 3603; b) T. Piou, L. Neuville, J. Zhu, Angew. Chem. Int. Ed. 2012, 51, 11561 – 11565; Angew. Chem. 2012, 124, 11729 – 11733; c) T. Piou, A. Bunescu, Q. Wang, L. Neuville, J. Zhu, Angew. Chem. Int. Ed. 2013, 52, 12385 – 12389; Angew. Chem. 2013, 125, 12611 – 12615. C H Activation: Topics in Current Chemistry, Vol. 292 (Eds.: J.-Q. Yu, Z.-J. Shi), Springer, Berlin, 2010. T. K. Devon, A. I. Scott, Handbook of Naturally Occurring Compounds, Vol. 1, Academic Press: New York, 1975, p 249. K. Knepper, R. E. Ziegert, S. Brse, Tetrahedron 2004, 60, 8591 – 8603 and references cited therein. D. Mal, P. Pahari, Chem. Rev. 2007, 107, 1892 – 1918. Copper salts screened: Cu(OTf)2, Cu(ClO4)2·6H2O, Cu(OAc)2, CuSO4, CuF2, Cu(EH)2, CuO, CuBr, Cu(NO3)·3H2O, CuOTf, Cu(MeCN)4BF4, Cu(MeCN)4PF6 ; oxidants screened: DTBP, tert-butyl hydroperoxide, tert-butyl benzoperoxoate, cumene hydroperoxide); ligands screened: pyridine, 2,2’-bipyridine, 4,4’-dimethoxybipyridine, 2,2’-bipyrimidine, neocuproine, 1,10phenanthroline, 4,5-diazafluoren-9-one, binol; bases screened: KOAc, K3PO4, KOAc, K2CO3, Na3PO4, Li3PO4, KH2PO4, CsOPiv. See the Supporting Information for details. a) H. Fischer, L. Radom, Angew. Chem. Int. Ed. 2001, 40, 1340 – 1371; Angew. Chem. 2001, 113, 1380 – 1414; b) A. R. Bader, R. P. Buckley, F. Leavitt, M. Szwarc, J. Am. Chem. Soc. 1957, 79, 5621 – 5625; c) F. M. Lewis, F. R. Mayo, J. Am. Chem. Soc. 1948, 70, 1533 – 1536. The results of these control experiments indicated that the nucleophilic addition of enolate to oxoammonium was less probable under our reaction conditions since the [bipy – Cu(OTf)2] system is incapable of oxidizing TEMPO to TEMPO + in acetonitrile, see: J. M. Hoover, B. L. Ryland, S. S. Stahl, J. Am. Chem. Soc. 2013, 135, 2357 – 2367. Cu prefers C-metalation with alkyl nitriles, see: a) M. Purzycki, W. Liu, G. Hilmersson, F. F. Fleming, Chem. Commun. 2013, 49, 4700 – 4702; b) Y. Suto, R. Tsuji, M. Kanai, M. Shibasaki, Org. Lett. 2005, 7, 3757 – 3760; c) J. Shen, D. Yang, Y. Liu, S. Qin, J. Zhang, J. Sun, C. Liu, C. Liu, X. Zhao, C. Chu, R. Liu, Org. Lett. 2014, 16, 350 – 353; D. Yang, Y. Liu, S. Qin, J. Zhang, J. Sun, C. Liu, C. Liu, X. Zhao, C. Chu, R. Liu, Org. Lett. 2014, 16, 350 – 353. C. L. Jenkins, J. K. Kochi, J. Am. Chem. Soc. 1972, 94, 843 – 855. Q. Xia, X. Liu, Y. Zhang, C. Chen, W. Chen, Org. Lett. 2013, 15, 3326 – 3329. a) M.-B. Zhou, R.-J. Song, X.-H. Ouyang, Y. Liu, W.-T. Wei, G.-B. Deng, J.-H. Li, Chem. Sci. 2013, 4, 2690 – 2694; b) S.-L. Zhou, L.-N. Guo, H. Wang, X.H. Duan, Chem. Eur. J. 2013, 19, 12970 – 12973. a) G. E. Morris, D. Oakley, D. A. Pippard, D. J. H. Smith, J. Chem. Soc. Chem. Commun. 1987, 411 – 412; b) R. T. Gephart III, C. L. McMullin, N. G. Sapiezynski, E. S. Jang, M. J. B. Aguila, T. R. Cundari, T. H. Warren, J. Am. Chem. Soc. 2012, 134, 17350 – 17353. For additional radical clock experiments, see the Supporting Information.
Received: September 2, 2014 Published online on October 5, 2014
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Communication
& Synthetic Methods
Copper-Mediated/Catalyzed Oxyalkylation of Alkenes with Alkylnitriles Ala Bunescu, Qian Wang, and Jieping Zhu*[a] Abstract: A copper-promoted oxyalkylation of alkenes with alkylnitriles has been developed. The protocol provides rapid access to phthalides (g-lactones) or isochromanones (d-lactones) via the formation of a C(sp3) C(sp3) and a C(sp3) O bond with the generation of up to two quaternary carbon atoms. Mechanistic studies suggest that this reaction is initiated by the formation of the C(sp3) C(sp3) bond rather than the C(sp3) O bond. Catalytic conditions were subsequently developed using carboxylic acid as an internal nucleophile.
The difunctionalization of alkenes represents a domain of major interest in organic synthesis due to the availability of the starting materials and the possibility to attain molecular complexity and diversity in one single step. Among the available methods, metal-catalyzed transformations have emerged as a powerful tool for this purpose.[1] However, C(sp3) C(sp3) bond formation remains challenging, mainly due to the competitive b-hydride elimination process.[2] In recent years, copper has gained much popularity as a catalyst for two important processes: the C(sp3) C(sp3) cross-dehydrogenative coupling (CDC)[3] and the difunctionalization of alkenes.[4–6] Regardless of remarkable achievements realized in the field, examples of copper-mediated/catalyzed difunctionalization of alkenes with generation of a C(sp3) C(sp3) bond remain rare.[7, 8] The formation of organometallic complexes (Ln, Rh, Fe, Ru) by activating a-C H bond of acetonitrile has been documented in the past.[9] Nevertheless, the use of nitrile with synthetic purpose is limited mainly to its enolate form[10, 11] requiring a strong base [pKa (MeCN) 31.3, DMSO] for its formation or the use of activated nitriles like b-cyanocarbonyls (pKa 13–14, DMSO) or a-arylacetonitriles (pKa 21.9, DMSO). Recently, Liu and co-workers reported an elegant Pd-catalyzed oxidative arylalkylation of alkenes involving an a-CH activation of acetonitrile using PhI(OCOtBu)2 (1.1 equiv) and AgF (4.0 equiv) as copromoters [Scheme 1, Eq. (1)].[2a] As a continuation of our ongoing project dealing with the metal-catalyzed C(sp3) H func[a] A. Bunescu, Dr. Q. Wang, Prof. Dr. J. Zhu Laboratory of Synthesis and Natural Product Institute of Chemical Sciences and Engineering Ecole Polytechnique Fdrale de Lausanne EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201405102. Chem. Eur. J. 2014, 20, 14633 – 14636
Scheme 1. Functionalization of alkenes with alkylnitriles.
tionalization,[12, 13] we report herein a copper mediated/catalyzed oxyalkylation of alkenes using alkylnitriles as reaction partners leading to functionalized phthalides and isochromanones [Scheme 1, Eq. (2)]. Phthalides are widely present in natural products[14] and pharmaceuticals,[15] and have proved useful as building blocks in organic synthesis.[16] Using N-(tert-butyl)-2-(prop-1-en-2-yl)benzamide (1 a, X = NHtBu) and acetonitrile as test substrates, conditions were surveyed by varying the copper salts, the oxidants, the ligands, the bases,[17] and the temperature. The initial conditions, which led to reasonable yield of 2 a, were as follows: Cu(OTf)2 (2.0 equiv), 1,10-phenanthroline (1.0 equiv), K3PO4 (2.0 equiv) and di-tert-butylperoxide (DTBP; 2.0 equiv) at 140 8C (for details, see the Supporting Information). Under these conditions, two oxyalkylation products, at the expense of isoindolinone resulting from the aminoalkylation process, were formed in 58 % yield (by NMR spectroscopy; 2 a/2 b = 1:1; Table 1, entry 1). Gratifyingly, by adding water (11.0 equiv) into the reaction mixture, the yield of oxyalkylation products increased with an improved ratio of 2 a to 2 b (isolated in 65 % yield; 2 a/2 b = 1.5:1; Table 1, entry 2). Further fine-tuning of the reaction conditions indicated that 2,2’-bipyridine was the ligand of choice (Table 1, entries 4–7). In these preliminary experiments, we also isolated nitrile 3, which could have important mechanistic implications (see below). Finally, the nature of the amide group (X = NHtBu, NHMe, or NMe2) impacted significantly the product yield (Table 1, entries 7–9). Using N,N-dimethylamide 1 c (X = NMe2) as starting material, phthalide 2 a was isolated as a sole product in 86 % yield (Table 1, entry 10). The yield of 2 a decreased significantly when Cu/ligand ratio was reduced to 1:1 (Table 1, entry 10).
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Communication Table 1. Oxyalkylation of alkenes: survey of reaction conditions.
Entry
X
Ligand
Base/Additive
Yield of 2 a [%][b]
1 2 3 4 5 6 7 8 9 10
NHtBu NHtBu NHtBu NHtBu NHtBu NHtBu NHtBu NHMe NMe2 NMe2
1,10-phen 1,10-phen 1,10-phen 1,10-phen pyridine bpym 2,2’-bipy 2,2’-bipy 2,2’-bipy 2,2’-bipy
K3PO4 K3PO4/water water KH2PO4/water K3PO4/water K3PO4/water K3PO4/water K3PO4/water K3PO4/water K3PO4/water
(58)[c] 65 (72)[c] degradation degradation (21) (38) 67 75 86 (31)[d]
[a] Reactions were carried out on 0.05 mmol scale in sealed tubes. Standard conditions: Cu(OTf)2 (2.0 equiv), Ligand (1.0 equiv), DTBP (2.0 equiv), Base (2.0 equiv), H2O (11.0 equiv), air, 140 8C, CH3CN (0.1 m). [b] Yield in parentheses is calculated based on 1H NMR spectra using CH2Br2 as an internal standard. [c] Mixture of 2 a and 2 b. [d] Ligand (2.0 equiv) was used. 1,10-phen = 1,10-phenanthroline; bpym = 2,2’-bipyrimidine; 2,2’-bipy = 2,2’-bipyridine; DTBP = di-tert-butyl peroxide.
The scope of the oxyalkylation of alkenes was next investigated using tethered N,N-dimethyl amide as an internal nucleophile (Scheme 2). The presence of an electron-withdrawing (F) or -donating group (Me, OMe, -OCH2O-) at different positions of aromatic ring (ring A) was tolerated (2 c–2 g). The reaction tolerated well the substituent at the b-position of the double bond (R2 = Me, Et, Ph), with the phenyl substituent leadng to an improvement in yield (2 i, 92 %). When a mixture of trisubstituted (Z)/(E)-2-(but-2-en-2-yl)-N,N-dimethylbenzamide (R2 = R3 = Me; Z/E = 4/1) was used, the desired phthalide 2 j was isolated in 55 % yield as a mixture of two diastereomers together with unreacted E isomer.[18] Gratifyingly, other alkyl nitrile, such as propionitrile, n-butyronitrile, n-valeronitrile and 3methoxypropionitrile, participated in this reaction to give the desired functionalized heterocycles in yields ranging from 66 % to 77 % (2 k–2 o; Scheme 2). More importantly, the reaction with isobutyronitrile resulted in the formation of phthalide 2 p in 65 % yield with concurrent generation of two quaternary carbon atoms. To our knowledge, this represented the first example wherein an a-substituted alkylnitrile participated in the metal-promoted addition reaction to alkenes. Interestingly, benzyl cyanide failed to participate in the oxyalkylation reaction with 1 c. When N,N-dimethyl-4-phenylpent-4-enamide was used as substrate, the desired g-lactone 2 q was obtained in 61 % yield (isolated product). Formation of g-lactone was also possible, as exemplified by the synthesis of isochromanone 2 r (69 %). The reaction of 1 c (X = NMe2) with MeCN was completely inhibited in the presence of a radical scavenger (TEMPO), with 2[(2,2,6,6-tetramethylpiperidin-1-yl)oxy]acetonitrile 4 being the only isolable product at the expense of alkoxyamine 5[5] (Scheme 3). This result, together with the isolation of alkene 3 in our initial experiments (Table 1), indicated that the domino Chem. Eur. J. 2014, 20, 14633 – 14636
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Scheme 2. Scope of oxyalkylation reaction: [a] Reactions were carried out on 0.1 mmol scale in sealed tubes. Conditions: Cu(OTf)2 (2.0 equiv), bipy (1.0 equiv), DTBP (2.0 equiv), K3PO4 (2.0 equiv), H2O (11.0 equiv), 140 8C. [b] Yield based on conversion.
Scheme 3. Radical trapping experiments. [a] Yield of isolated product. [b] Yield by NMR spectroscopy.
oxyalkylation of 1 c leading to phthalides 2 was initiated by the formation of the C C bond rather than the C O bond.[5] Performing the radical trapping experiment in the absence of Cu(OTf)2 or K3PO4 failed to produce compound 4 (Scheme 3, exp. 2 and 3). The presence of both salts was therefore essential to the activation of acetonitrile. In contrast, compound 4 was formed in 51 % yield (by NMR) in the absence of DTBP indicating that DTBP was not essential for acetonitrile activation (Scheme 3, exp. 4). Indeed, the oxyalkylation proceeded in the absence of DTBP under otherwise identical conditions, although the reaction stopped at 40 % conversion even in the presence of two equivalents of Cu(OTf)2. In addition, 4 was generated in a similar yield when the last control experiment
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Communication was repeated under a strictly inert atmosphere (Scheme 3, exp. 5).[19] Taking into consideration the above results, possible reaction pathways leading to phthalide 2 are depicted in Scheme 4. Co-
that the oxyalkylation of 1 d could indeed take place under catalytic conditions (see the Supporting Information for details of the optimization of reaction conditions). Under optimum conditions [Cu(OAc)2 (0.3 equiv), 1,10-phen (0.3 equiv), Na3PO4 (2.0 equiv), DTBP (2.0 equiv), 140 8C, N2, 3 h], reaction of 1 d and MeCN afforded 2 a in 77 % yield. The catalytic conditions turned out to be quite general (Scheme 5). The reaction was
Scheme 4. Possible reaction pathways.
ordination of copper(II) triflate to nitrile followed by deprotonation of the complex A by potassium phosphate would produce the organocopper species B[20] that, after homolytic cleavage of the C CuII bond, would deliver the cyanomethyl radical C. Radical addition to alkene 1 c would produce the benzylic radical D. Intermediate D could be further oxidized to a cationic intermediate E,[21] which upon cyclization afforded F. Formation of an organocopper(III) intermediate G from D followed by reductive elimination could also provide intermediate F. Alternatively, the reaction could also be initiated by carbocuppration of 1 c by B leading to H which could subsequently be oxidized to intermediate G. Finally, hydrolysis of the carboximidate salt F furnished phthalide 2 a. Oxidation of CuI with DTBP would regenerate the CuII salt.[7c, 22–24] To gain insight on whether the reaction was initiated by carbocupration or by radical addition process, the following control experiments were performed. Both 2-cyclopropylacetonitrile (6) and 2-(1-cyclopropylvinyl)-N,N-dimethylbenzamide (7), failed to participate in this reaction, whereas the reaction of 8 with acetonitrile under standard conditions afforded the lactone 2 s, albeit with a reduced yield (34 %).[25] Although the results of these cyclopropane radical clock experiments, together with the lack of diastereoselectivity in the formation of 2 j from its Z-olefinic precursor seemed in favor of a radical process (Scheme 4, pathway a), the alternative carbocupration process (Scheme 4, pathway b) cannot be discarded at the present stage of development. The reason why 2 equivalents of Cu(OTf)2 was needed to drive the reaction to completion is at present unclear. We hypothesized that the amide function of the starting material, as well as the in situ-generated dimethylamine might coordinate strongly to Cu leading to catalyst poisoning. With this rationale in mind, we investigated the reaction between 2-(prop-1-en-2yl)benzoic acid (1 d) and acetonitrile. We were pleased to find Chem. Eur. J. 2014, 20, 14633 – 14636
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Scheme 5. Oxyalkylation of alkenes with alkylnitriles under catalytic conditions. [a] Conditions: Cu(OAc)2 (0.3 equiv), 1,10-phen (0.3 equiv), Na3PO4 (2.0 equiv), DTBP (2.0 equiv in 2 portions), N2, 140 8C.
insensitive to the electronic properties of the aromatic ring and was operational with trisubstituted olefin leading to compound 2 j. Propionitrile and butyronitrile reacted with 1 d to produce the corresponding phthalides 2 k and 2 t, albeit with reduced yields relative to the stoichiometric process. The g-lactone can also be produced as evidenced by the synthesis of isochromanone 2 r (58 %). In summary, we developed a simple Cu-promoted/catalyzed oxyalkylation of alkenes with alkyl nitriles. This unprecedented reaction afforded an efficient access to 3,3-disubstituted phthalides and isochromanones through the formation of a C(sp3) C(sp3) and a C(sp3) O bond. The reaction displayed a wide application scope and up to two quaternary carbon atoms could be generated in this process. Preliminary mechanistic studies suggested that the formation of alkylcuprate intermediate by the dual action of copper salt and potassium phosphate is key to the present process. To our knowledge, this report represents the first examples of alkylative lactonization of alkenes by unactivated alkylnitriles.
Experimental Section Catalytic process: To a mixture of acid 1 (1.0 equiv), Cu(OAc)2 (0.3 equiv), 1,10-phen (0.3 equiv) and Na3PO4 (2.0 equiv) in RCN (0.1 m) was added DTBP (1.0 equiv) and the tube was sealed and stirred at 140 8C under N2 atmosphere for 90 min. The reaction mixture was cooled to room temperature, a second portion of DTBP
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Communication (1.0 equiv) was added, and the tube was sealed and stirred at 140 8C under N2 atmosphere for an additional 90 min. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford heterocycle 2.
[9]
Acknowledgements
[10]
Financial support from EPFL (Switzerland) and the Swiss National Science Foundation (SNSF) is gratefully acknowledged.
[11]
Keywords: alkenes oxyalkylation
[12]
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alkylation
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copper
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lactones
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Received: September 2, 2014 Published online on October 5, 2014
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