Nickel-Catalyzed Reductive Dicarbofunctionalization of Alkenes

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Nickel-Catalyzed Reductive Dicarbofunctionalization of Alkenes Andrés García-Domínguez, Zhaodong Li, and Cristina Nevado* Department of Chemistry, University of Zurich, Winterthurerstrasse 190, Zurich CH 8057, Switzerland S Supporting Information *

reductive alkene dicarbofunctionalization reaction that combines alkyl and aryl iodides to produce, in a single synthetic operation, two new C−C bonds by their sequential addition onto both, activated and unactivated alkenes, in the presence of a metal-free reductant (Scheme 1B).

ABSTRACT: An intermolecular, three-component reductive dicarbofunctionalization of alkenes is presented here. The combination of Ni catalysis with TDAE as final reductant enables the direct formation of Csp3−Csp3 and Csp3−Csp2 bonds across a variety of π-systems using two different electrophiles that are sequentially activated with exquisite selectivity under mild reaction conditions.

Scheme 1. Strategies toward Dicarbofunctionalization of Alkenes

D

icarbofunctionalization of olefins by simultaneous addition of two carbon groups across the double bond has attracted increasing attention in recent years given not only the availability of alkenes from natural sources but also the added value of the resulting products. Classical methods include Michael-type additions of sensitive organometallic reagents to activated olefins followed by enolate trapping with electrophiles.1 Alternatively, transition metal catalyzed approaches have also been developed. In particular, the use of Pd-catalysis for the regioselective dicarbofunctionalization of dienes involving Csp2-reagents has found broad applicability and even asymmetric versions of these transformations have been realized (Scheme 1A, top).2 In contrast, reactions involving the addition of alkyl groups across alkenes are much less developed given the number of side reactions that Csp3-metal reagents and intermediates can undergo, including β-hydride elimination, homocoupling, isomerization or protodemetalation. To the best of our knowledge, only a handful of reports dealing with the intermolecular dicarbofunctionalization of alkenes using Csp3-reagents have been reported to date.3 In this context, in the presence of a Ni catalyst, activated alkenes have been used as acceptors and redox active esters and difluoroalkyl bromides in combination with aryl zinc4 and aryl boron5 reagents, respectively, could be successfully added across the π-system (Scheme 1A, bottom). From a formal point of view, all of the above-mentioned methods rely on the addition of a nucleophile and an electrophile across activated πsystems. On the other hand, reductive couplings have recently gained substantial attention as they represent a unique tool to handle Csp3-based reagents and allow reactions under mild conditions without any additional prefunctionalization compared to classical cross-coupling methodologies.6 Taking into account the potential of these transformations and our ongoing interest in the development of multicomponent reactions for the efficient difunctionalization of multiple bonds,7 we envisioned the possibility of adding two different carbon-based electrophiles across alkenes taking advantage of the ability of Ni catalysts to activate both Csp2− as well as Csp3−halogen bonds. Here, we present the first example of an intermolecular © 2017 American Chemical Society

Allyl acetate, tert-butyl iodide and 4-tert-butyliodobenzene were chosen as benchmark substrates to find the optimal conditions for this multicomponent reaction (Table 1). Following initial optimization,8 different reductants were assayed in the presence of 10 mol% of NiCl2·DME and dtbbpy (L1 = 4,4′-di-tert-butyl-2,2′-bipyridine). Although Zn, Mn and B2pin2/tBuOK9 did not produce the desired product (Table 1, entries 1−3), the reaction in the presence of TDAE (tetrakis(dimethylamino)ethylene) produced 1 in a promising 17% yield (Table 1, entry 4).10 Different ligands were examined next: 2,2′-bipyridine (L2), phenanthroline (L3) or 4′-p-tolylterpyridine (L4) did not improve the reaction outcome (Table 1, entries 5−7). The influence of the Ni catalysts was also explored. In the presence of L1 and TDAE as reductant, NiBr2· DME furnished 1 in 54% yield whereas Ni(acac)2 proved to be less efficient (Table 1, entries 8 and 9). Fortunately, the use of Received: March 30, 2017 Published: May 10, 2017 6835

DOI: 10.1021/jacs.7b03195 J. Am. Chem. Soc. 2017, 139, 6835−6838

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Journal of the American Chemical Society Table 1. Optimization of the Reaction Conditionsa

entry

Ni

ligand

additive

yield of 1 (%)b

1 2 3 4 5 6 7 8 9 10 11 12

NiCl2·DME NiCl2·DME NiCl2·DME NiCl2·DME NiCl2·DME NiCl2·DME NiCl2·DME NiBr2·DME Ni(acac)2 NiCl2(Py)4 − NiCl2(Py)4

L1 L1 L1 L1 L2 L3 L4 L1 L1 L1 L1 −

Zn Mn B2pin2/KOtBu TDAEc TDAEc TDAEc TDAEc TDAEc TDAEc TDAEc − TDAEc

0 0 0 17 1 2 0 54 27 82 (83) 0 0

Scheme 2. Reaction Scope

a

Conditions: Ni/L (10 mol %), allyl acetate (1 equiv), p-tBuC6H4I (2 equiv), tBuI (1.5 equiv), additive (2 equiv), THF (0.4 M), 25 °C. b Yield determined by 1H NMR with 4-nitroacetophenone as internal standard. In brackets: isolated yield after column chromatography. c TDAE (2.15 equiv).

NiCl2(Py)4 delivered compound 1 in 83% optimized yield (Table 1, entry 10). Both, the Ni complex and the ligand, played a critical role in the reaction as shown by entries 11 and 12. With the optimized reaction conditions in hand (Table 1, entry 10), we set out to explore the scope of this transformation (Scheme 2). First, different aryl iodides were investigated. Phenyl, p-tolyl, p-methoxy and p-fluoro substituted iodobenezenes could be efficiently coupled under the standard reaction conditions producing compounds 2−5 in moderated to good yields. Substitution in meta position with both electrondonating as well as electron-withdrawing groups was also well tolerated as demonstrated by the efficient conversion obtained for 6−10. The functional group compatibility was further investigated. Products 11, 12 and 13 highlight the orthogonality of this method with respect to classical Pd-catalyzed reactions as Csp2−Br, Csp2−Cl and Csp2−B moieties were accommodated under these conditions producing the corresponding addition products in good yields. Steric factors seem to have an impact in the reaction outcome, as ortho-substituted phenyl ketone derivative 14 could only be isolated in 29% yield. The compatibility of the method with different types of olefins was investigated next. Allylic alcohols, phosphonates, anilines and amides proved to be amenable substrates under the reported conditions producing 15−18 in synthetically useful yields. Highly efficient reactions were obtained in the case of activated olefins such as enol esters or enamides as demonstrated by the synthesis of 19 and 20 in 81 and 65% yield, respectively. Michael acceptors proved to be successfully transformed under the optimal conditions as shown by the high yields in which compounds 21−24 could be isolated. A more complex epiandrosterone derivative could also be efficiently engaged in the reaction as shown by the successful isolation of

a

Standard reaction conditions: Table 1, entry 10. Isolated yields after column chromatography are given. bUnless otherwise stated, Rn = H. c Ni/L (20 mol %), Alkyl-I (2 equiv). dMixture of diastereoisomers 1:1.

25 in 53% yield. Crotononitrile (E:Z = 4:1) delivered the corresponding addition products 26−29 with high levels of diastereoselectivity, thus demonstrating the compatibility of the reaction conditions with internal olefins. The relative configuration of the major isomer could be confirmed by successful X-ray diffraction analysis of compound 29.8 Interestingly, alkynes could also be successfully engaged in this dicarbofunctionalization reaction producing the corresponding trisubstituted alkenes 30−32 as single stereoisomers as a result of the formal anti-addition of the two electrophiles across the π-system. Finally, different unactivated tertiary alkyl iodides, including those bearing Csp3−Cl bonds, could also be incorporated as shown in compounds 33−37. Unfunctionalized olefins did not engage in the reaction, thus highlighting the importance of a coordinating/directing group for a successful outcome.11 Control experiments were designed to uncover the reaction mechanism (Scheme 3). Addition of BHT, 1,1-diphenylethylene or 1,4-cyclohexadiene significantly reduced the reaction’s efficiency (data not shown, see section 5 in the SI). Moreover, experiments involving radical clocks were also revealing: while in the presence of unactivated alkenes, the cyclization of the alkyl iodide 38 to give 39 is favored over the intermolecular addition onto allyl acetate,12 the reaction in the presence of acrylonitrile delivered addition product 40 in 45% 6836

DOI: 10.1021/jacs.7b03195 J. Am. Chem. Soc. 2017, 139, 6835−6838

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Journal of the American Chemical Society Scheme 3. Control Experiments

Scheme 4. Proposed Reaction Mechanism

adds onto the alkene to produce D. Radical intermediate D can then combine with A to produce the key Ni(III) species B (path I).14 Complex B undergoes reductive elimination to produce the corresponding dicarbofunctionalization product and Ni(I), which in the presence of either AlkI or TDAE regenerates Ni(II) or Ni(0) respectively, thus closing the catalytic cycle.15 In situ formation of secondary alkyl iodides (E) as putative reaction intermediates (path II) seems to be ruled out based on all control experiments (Scheme 3, eqs 2, 3 and 5). Furthermore, the fact that no reaction occurs in the absence of Ni and ArI (Scheme 3, eqs 5 and 6) and the successful reaction of complex 43 (eq 8) suggest the participation of ArNi(II) species (A) in these transformations. Although alternative mechanisms cannot be excluded, the lack of Alk-Ar direct coupling products under the reaction conditions seems to rule out the participation of ArAlkNi(III) intermediates,16 either resulting from the direct recombination of tertiary alkyl radicals C with intermediate A, or from the oxidative addition of ArI with in situ produced AlkNi(I) species.17 In conclusion, the first example of an intermolecular, threecomponent reductive dicarbofunctionalization of alkenes under mild reaction conditions using nickel catalysis is presented here. The use of TDAE as an organic reductant is crucial, as it avoids the generation of stoichiometric metallic waste and makes the procedure operationally simple. In this process, two new C−C bonds are formed in one-pot (1 × Csp3−Csp3 and 1 × Csp3− Csp2) by addition of two different electrophiles across the πsystem thus expanding the scope of existing dicarbofunctionalization reactions. In addition, this method represents a mechanistically distinct approach to functionalize alkenes through the selective activation of two different electrophiles based on their distinct reactivity toward Ni species in different oxidation states.

yield with 39 not being detected in the reaction media (eqs 1 and 2). These results are consistent with the kinetic data for both processes (cyclization of a C-centered radical onto a monosubstituted alkene vs intermolecular addition onto an activated olefin) previously reported in the literature,13 and suggest the presence of C-centered radicals along the reaction pathway. The involvement of secondary alkyl iodides as potential reaction intermediates was investigated next. Monitoring the standard reaction shown in Table 1 by 1H NMR and GC−MS over time showed no formation of alkyl iodide at any stage of the reaction (data not shown, see section 5 in the SI). Further, alkyl iodide 41 displayed no reactivity under the standard reaction conditions (eq 3). Interestingly, no reaction was observed in the absence of alkyl iodides (eq 4) whereas activation of the alkyl iodide in the absence of ArI seems to be possible only to a very limited extent (eq 5). The presence of Ni, in contrast, seems to be crucial for the process (eq 6). The role of the reductant was also investigated. The reaction of Ni(dtbbpy)I2 with TDAE in the presence of 2-iodotoluene delivered the corresponding ArNi(II) complex 42,6d demonstrating the ability of TDAE to reduce Ni(II) complexes followed by a successful oxidative addition (eq 7). Interestingly, the stoichiometric reaction of ArNi(II) complex 43 (derived from 4-tert-butylchlorobenzene and L1) with acrylonitrile, tertbutyl iodide, in the presence of TDAE furnished the desired product 24 in 55% yield, thus proving the competence of ArNi(II) species as potential reaction intermediates in these transformations (eq 8). Based on the above-mentioned experimental evidence, the following mechanism can be proposed (Scheme 4). Under the reductive reaction conditions, Ni(0) species generated in situ can undergo oxidative addition onto the ArI moiety to produce ArNi(II) intermediate A (eq 7). In parallel, Ni(I) species produced in the reaction media could be responsible for the activation of the alkyl iodide to produce an alkyl radical C that

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b03195. Compound synthesis, characterization and additional experiments (PDF) 6837

DOI: 10.1021/jacs.7b03195 J. Am. Chem. Soc. 2017, 139, 6835−6838

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Journal of the American Chemical Society

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(8) For additional experiments, see Supporting Information. CCDC1540663 (29) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ structures. (9) (a) Xu, H.; Zhao, C.; Qian, Q.; Deng, W.; Gong, H. Chem. Sci. 2013, 4, 4022. (b) Fujita, T.; Arita, T.; Ichitsuka, T.; Ichikawa, J. Dalton Trans. 2015, 44, 19460. (10) For previous reports combining TDAE with nickel catalysis, see: (a) Anka-Lufford, L.; Huihui, K. M. M.; Gower, N. J.; Ackerman, L. K. G.; Weix, D. J. Chem. - Eur. J. 2016, 22, 11564. (b) Kuroboshi, M.; Tanaka, M.; Kishimoto, S.; Goto, K.; Mochizuki, M.; Tanaka, H. Tetrahedron Lett. 2000, 41, 81. (c) Broggi, J.; Terme, T.; Vanelle, P. Angew. Chem., Int. Ed. 2014, 53, 384. (11) The reaction with aryl bromides proceeded, albeit with lower efficiency. Primary and secondary alkyl iodides could not be successfully coupled. For these and additional examples exploring the reaction scope, see section 6 in the Supporting Information. (12) Newcomb, M.; Filipkowski, M. A.; Johnson, C. C. Tetrahedron Lett. 1995, 36, 3643. (13) Fischer, H.; Radom, L. Angew. Chem., Int. Ed. 2001, 40, 1340. (14) Biswas, S.; Weix, D. J. J. Am. Chem. Soc. 2013, 135, 16192. (15) TDAE is transformed into [TDAE2+][I−]2 under the reaction conditions. For this and additional control experiments on the role of TDAE and other reductants, see section 5 in the Supporting Information. (16) (a) Gutierrez, O.; Tellis, J. C.; Primer, D. N.; Molander, G. A.; Kozlowski, M. C. J. Am. Chem. Soc. 2015, 137, 4896. (b) Schley, N. D.; Fu, G. C. J. Am. Chem. Soc. 2014, 136, 16588. (17) For selected references on recent Ni-catalyzed reactions invoking radical intermediates, see: (a) Schmidt, J.; Choi, J.; Liu, A. T.; Slusarczyk, M.; Fu, G. C. Science 2016, 354, 1265. (b) Wang, J.; Chen, T.-G.; Wimmer, L.; Edwards, J. T.; Cornella, J.; Vokits, B.; Shaw, S. A.; Baran, P. S.; Qin, T. Angew. Chem., Int. Ed. 2016, 55, 9676. (c) Zhang, X.; MacMillan, D. W. C. J. Am. Chem. Soc. 2016, 138, 13862. (d) Matsui, J. K.; Primer, D. N.; Molander, G. A. Chem. Sci. 2017, DOI: 10.1039/C7SC00283A.

AUTHOR INFORMATION

Corresponding Author

*[email protected] Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the European Research Council (ERC Starting grant agreement no. 307948) and the Swiss National Science Foundation (SNF 200020_146853) for financial support. We also thank Prof. Anthony Linden for the X-ray diffraction analysis of 29.

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DOI: 10.1021/jacs.7b03195 J. Am. Chem. Soc. 2017, 139, 6835−6838