Letter pubs.acs.org/OrgLett
Light-Induced Alkylation of (Hetero)aromatic Nitriles in a TransitionMetal-Free C−C-Bond Metathesis Benjamin Lipp,† Alexander Lipp,† Heiner Detert, and Till Opatz* Institute of Organic Chemistry, University of Mainz, Duesbergweg 10-14, D-55128 Mainz, Germany S Supporting Information *
ABSTRACT: A light-induced C−C-σ-bond metathesis was achieved through transition-metal-free activation of an unstrained C(sp 3 )−C(sp 3 )-σ-bond in 1-benzyl-1,2,3,4tetrahydroisoquinolines. A photoredox-mediated single-electron oxidation of these precursor amines yield radical cations which undergo a homolytic cleavage of a C(sp3)−C(sp3)-σbond rather than the well-known α-C−H-scission. The resulting carbon-centered radicals are used in the ipso-substitution of (hetero)aromatic nitriles proceeding through another single-electron transfer-mediated C−C-bond cleavage and formation.
D
Scheme 1. Reactions Involving a Cleavage of an Unstrained C(sp3)−C(sp3)-σ-Bond in 1,2-Dihydro- and 1,2,3,4Tetrahydroisoquinolines
ue to their thermodynamic stability and their low degree of polarization, the activation of unstrained C−C-bonds is still among the most difficult challenges in organic chemistry.1 Significant progress has been made in this field in recent decades, yet most examples rely on the use of transition metals.1,2 The cleavage of unstrained C(sp3)−C(sp3)-σ-bonds is particularly demanding, and relatively few examples are known to date.1 A possible strategy for the cleavage of such strong bonds is the fragmentation of radical cations.3 In 1963, Knabe and co-workers reported an acid-promoted, stereospecific rearrangement of N-methyl-1,2-dihydropapaverine (Scheme 1a).4 Kinetic studies by Langhals and Rüchardt5 provided strong evidence for a radical chain reaction via the homolytic cleavage of an unstrained C(sp3)−C(sp3)-σ-bond in an intermediate radical cation.6 We have found a related 1,3benzyl migration in 1-benzyl-1,2,3,4-tetrahydroisoquinolines (Scheme 1b) and, together with the Straub group, presented evidence for a free radical chain mechanism under kinetic entropy control.7 Again, a homolytic cleavage of an unstrained C(sp3)−C(sp3)-σ-bond is involved. It is well established that light-induced single-electron transfer (SET) reactions provide access to radical cations under exceptionally mild conditions.3a Over the past decade, photoredox catalysis has emerged as one of the most vital research areas within organic chemistry.8 Upon excitation by light, a photoredox catalyst (e.g., transition metal complex,9 organic dye,10 or semiconductor11) undergoes two successive SET steps, thereby returning to its electronic ground state. By engaging in these redox reactions, components of the reaction mixture can experience unique, net redox-neutral transformations.8 N-Substituted 1,2,3,4-tetrahydroisoquinolines belong to the most frequently used electron donors in photoredox-catalyzed reactions.8,12 The initially formed amine radical cations are usually converted to the corresponding iminium ions by abstraction of a hydrogen atom or by deprotonation and subsequent one-electron oxidation of the resulting neutral radical.12 © 2017 American Chemical Society
With the mentioned previous work on σ-bond fragmentation taken into consideration (Scheme 1b), the installation of a suitable 1-substituent on the tetrahydroisoquinoline core should favor the cleavage of a C(sp3)−C(sp3)-σ-bond over the scission of the adjacent α-C−H bond upon abstraction of an electron from nitrogen. The produced alkyl radicals could subsequently engage in a C−C-bond-forming reaction with a suitable radical acceptor. The radical ipso-substitution of Received: March 3, 2017 Published: April 7, 2017 2054
DOI: 10.1021/acs.orglett.7b00652 Org. Lett. 2017, 19, 2054−2057
Letter
Organic Letters Scheme 2. Plausible Reaction Mechanism of the Designed C−C-σ-Bond Metathesis
(hetero)aromatic nitriles would be an option in this respect.13 The combination of both processes would result in the net redox-neutral formation of a new C(sp3)−C(sp3)-σ-bond when light-induced SET steps serve to form both a transient (from the σ-bond fragmentation) and a persistent radical (from the reduction of the cyanoarene) which undergo a selective recombination (Scheme 1c).14 Ideally, the cyanide anion liberated in the rearomatization of intermediate 7a subsequently combines with iminium salt 5a to form αaminonitrile 9a, completing a new type of σ-bond metathesis in which two C−C bonds are broken and two new C−C bonds are formed. To the best of our knowledge, this constitutes the first report of a light-induced C−C-σ-bond metathesis. A mechanistic proposal for the designed reaction is depicted in Scheme 2. Upon excitation by UV-light, aromatic nitriles such as dicyanobenzenes and cyanopyridines become strong electron acceptors.13 It can thus be anticipated that excited 4cyanopyridine [E1/2(3[1a]*/2a) = +1.65 V vs SCE, calculated for the triplet state according to the literature, consequently higher for the singlet state]15 is capable of directly oxidizing 1,2dialkylated 1,2,3,4-tetrahydroisoquinolines such as (±)-laudanosine [3a, typically: E1/2(R3N•+/R3N) ≤ +1.1 V vs SCE15c and E1/2(4a/3a) = +0.55 V vs Ag/AgNO3/+0.86 V vs SCE16] to the corresponding radical cations 4a without any external photoredox catalyst being added. Alternatively, phenanthrene can be used as a photoredox catalyst, which proved to be suitable for radical alkylations of aromatic nitriles.17 Fluorescence quenching experiments17a indicate that the excited singlet state of phenanthrene [E1/2(Phen•+/1[Phen]*) = −2.1 V vs SCE]18 readily reduces aromatic nitriles such as 4-cyanopyridine [1a, E1/2(1a/2a) = −1.66 V vs SCE]15b to the corresponding radical anions 2a (oxidative quenching). The resulting phenanthrene radical cation is a strong electron acceptor [E1/2(Phen•+/Phen) = +1.50 V vs SCE]15c capable of oxidizing tertiary amines such as (±)-laudanosine (3a).15c Fluorescence quenching studies19 also suggest that the excited singlet state of phenanthrene [E1/2(1[Phen]*/Phen•−) = +1.14 V vs SCE, calculated according to the literature]15a,c is capable of oxidizing tertiary amines such as 3a to the corresponding radical cations
(reductive quenching). The emerging phenanthrene radical anion is a strong reductant [E1/2(Phen/Phen•−) = −2.44 V vs SCE]15c and easily transfers an electron to aromatic nitriles such as 4-canopyridine (1a). Cleavage of a C(sp3)−C(sp3)-σbond in the intermediate radical cation 4a and subsequent selective radical recombination, followed by elimination of cyanide from the anionic intermediate 7a and trapping of iminium ion 5a by liberated cyanide anions, finally affords pyridine 8a and α-aminonitrile 9a.14,17,20 A detailed mechanistic discussion is provided in the Supporting Information. An extensive screening of reaction conditions was undertaken using 4-cyanopyridine (1a) and (±)-laudanosine (3a) as a model system (see the Supporting Information, Tables S1− S6, S10). Although ipso-substitution product 8a could be obtained in the absence of an additional photoredox catalyst (36% yield, via direct SET, see Scheme 2), improved results were obtained in the presence of phenanthrene (25 mol %, 45% yield). α-Aminonitrile 9a is kinetically labile and reforms iminium ion 4a, which then competes with the nitrile’s radical anions 2a for the liberated benzylic radicals 6a or can engage in further photochemistry. Thus, the yield of 8a could be further increased by the addition of TMSCN (2.0 equiv, 64% yield) as an external cyanide source to improve trapping of the intermediate iminium ion 5a (see the Supporting Information, Table S10). TMSCN was found to be superior to KCN, presumably due to its excellent solubility in organic solvents such as acetonitrile (see the Supporting Information, Table S4). Based on unchanged UV/vis-absorption spectra, a potential coordination of the pyridine’s nitrogen to the TMS group, which would significantly lower the pyridine’s LUMO, appears unlikely (see the Supporting Information, section 4). Under the optimized conditions, the scope of this unprecedented reaction was investigated (Scheme 3). Since a longer lifetime of the radicals 6 should increase their probability of coupling with the cyanoarene-derived radical anions 2, an increase in yields of ipso-substitution products 8 with the increase in stability of the intermediate alkyl radicals was expected. Moreover, a higher stabilization of radicals 6 would also favor their liberation from the parent amine radical cations 2055
DOI: 10.1021/acs.orglett.7b00652 Org. Lett. 2017, 19, 2054−2057
Letter
Organic Letters Scheme 3. Scope of the Light-Induced Alkylation of (Hetero)aromatic Nitriles in a C−C-Bond Metathesisa
a
All reactions were performed according to the general procedure (see the Supporting Information). All yields are those of isolated products. bAfter purification via preparative HPLC. cIrradiation with sunlight. dUsing 1-(3,4-dimethoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline as a radical precursor. e0.80 mmol scale, simultaneously irradiated with two CFL bulbs. fProduct not isolated.
4 over the competing α-C−H-activation. Indeed, a range of precursors of secondary benzylic radicals furnished the desired alkylation products 8b−8d in high yields (70−75%). The reaction proceeded smoothly using methoxy-substituted, primary benzylic radicals (as liberated from natural benzylisoquinoline alkaloids) affording compounds 8a, 8e, and 8f in yields of 44−64%. The reaction of 4-cyanopyridine (1a) with (±)-laudanosine (3a) could also be effected using sunlight as the sole energy source (66% yield).21 Replacing the 3′,4′methoxy groups by alkyl moieties afforded moderate yields (43−48%, 8g and 8h), most likely due to the lower stability of the intermediate radicals. Remarkably, even unsubstituted benzylic radicals can serve as intermediates in the σ-bond metathesis, although the yield can be increased by extension of the arene moiety (8i vs 8j). Electron-withdrawing substituents in the benzylic radical (8u and 8v) and nonstabilized alkyl radicals (8w) are however not tolerated. Compound 8a could also be obtained using 1-(3,4-dimethoxybenzyl)-2-methyl1,2,3,4-tetrahydroisoquinoline as a radical precursor (58% yield) proving that the electron-donating 6,7-dimethoxy
substitution pattern at the tetrahydroisoquinoline core is not a prerequisite for this unusual C−C-bond cleavage. A range of alkylated and arylated cyanopyridines afforded the desired products 8k−8n in high yields (62−71%). Electronwithdrawing substituents in the pyridine core were tolerated as well (8o). Even the selective replacement of cyanide in the presence of a chlorine substituent in an activated position could be achieved (8p; loss of chlorine or double alkylation not observed). When 2-cyanopyridines were submitted to the standard procedure (8q and 8r), the desired products were obtained in moderate yields (27−34%), which are satisfactory in view of the largest LUMO-coefficient usually being located in the 4-position of the pyridine core.6,17b The ipso-substitution protocol was also successfully applied to 1-cyanoisoquinoline (8s). While 9,10-dicyanoanthracene afforded the desired product in moderate yield (8t, 27%), 1,4-dicyanobenzene did not engage in the C−C-bond-metathesis (8y). The alkylation of cyanopyridines bearing strongly electron-donating substituents is not feasible (8x), presumably due to their poor electron acceptor quality or the low stability of intermediate 2. 2056
DOI: 10.1021/acs.orglett.7b00652 Org. Lett. 2017, 19, 2054−2057
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Organic Letters
(8) Shaw, M. H.; Twilton, J.; MacMillan, D. W. C. J. Org. Chem. 2016, 81, 6898. (9) (a) Courant, T.; Masson, G. J. Org. Chem. 2016, 81, 6945. (b) Lenhart, D.; Bauer, A.; Pöthig, A.; Bach, T. Chem. - Eur. J. 2016, 22, 6519. (c) Xie, J.; Li, J.; Weingand, V.; Rudolph, M.; Hashmi, A. S. K. Chem. - Eur. J. 2016, 22, 12646. (d) Kelly, C. B.; Patel, N. R.; Primer, D. N.; Jouffroy, M.; Tellis, J. C.; Molander, G. A. Nat. Protoc. 2017, 12, 472. (10) Romero, N. A.; Nicewicz, D. A. Chem. Rev. 2016, 116, 10075. (11) Manley, D. W.; Walton, J. C. Beilstein J. Org. Chem. 2015, 11, 1570. (12) Hu, J.; Wang, J.; Nguyen, T. H.; Zheng, N. Beilstein J. Org. Chem. 2013, 9, 1977. (13) (a) Frolov, A. N. Russ. J. Org. Chem. 1998, 34, 139. (b) Bonesi, S. M.; Fagnoni, M. Chem. - Eur. J. 2010, 16, 13572. (14) Studer, A. Chem. - Eur. J. 2001, 7, 1159. (15) (a) Tucker, J. W.; Stephenson, C. R. J. J. Org. Chem. 2012, 77, 1617. (b) Cyr, D.; Das, P. Res. Chem. Intermed. 2015, 41, 8603. (c) Murov, S. L.; Carmichael, I.; Hug, G. L. Handbook of Photochemistry, 2nd ed.; Marcel Dekker Inc.: New York, 1993. (16) Miller, L. L.; Stermitz, F. R.; Becker, J. Y.; Ramachandran, V. J. Am. Chem. Soc. 1975, 97, 2922. (17) (a) Itou, T.; Yoshimi, Y.; Morita, T.; Tokunaga, Y.; Hatanaka, M. Tetrahedron 2009, 65, 263. (b) Lipp, B.; Nauth, A. M.; Opatz, T. J. Org. Chem. 2016, 81, 6875. (18) Iwai, K.; Takemura, F.; Furue, M.; Nozakura, S.-i. Bull. Chem. Soc. Jpn. 1984, 57, 763. (19) Chen, J. M.; Ho, T. I.; Mou, C. Y. J. Phys. Chem. 1990, 94, 2889. (20) (a) Zuo, Z.; MacMillan, D. W. C. J. Am. Chem. Soc. 2014, 136, 5257. (b) Orejarena Pacheco, J. C.; Lipp, A.; Nauth, A. M.; Acke, F.; Dietz, J.-P.; Opatz, T. Chem. - Eur. J. 2016, 22, 5409. (21) Nauth, A. M.; Lipp, A.; Lipp, B.; Opatz, T. Eur. J. Org. Chem. 2016, ahead of print (doi: 10.1002/ejoc.201601394). (22) Nakajima, K.; Nojima, S.; Sakata, K.; Nishibayashi, Y. ChemCatChem 2016, 8, 1028.
Finally, an iridium-based photoredox catalyst was tested in place of phenanthrene, which would allow the process to be induced by visible light.22 Again, an extensive optimization was undertaken (see the Supporting Information, Tables S7−S9). The visible-light-induced reaction proceeded smoothly with facIr(ppy)3 (1.5 mol %), although the yields were lower than those for the phenanthrene-based protocol (up to 53%). In summary, the cleavage of an unstrained C(sp3)−C(sp3)-σbond in 1-substituted N-alkyltetrahydroisoquinolines could be effected by means of a light-induced single-electron oxidation. This constitutes a new reaction mode of this substance class, being among the most common electron donors in photoredox-catalyzed transformations. The alkyl radicals arising from this C−C-bond cleavage could exemplarily be used in the ipsosubstitution of (hetero)aromatic nitriles proceeding through another single-electron transfer-mediated C−C-bond cleavage and formation. Overall, two C−C-bonds are formed at the expense of two others, which represents the first example of a light-induced C−C-σ-bond metathesis.
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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/acs.orglett.7b00652. Optimization studies, experimental procedures, a mechanistic discussion, and copies of NMR spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Till Opatz: 0000-0002-3266-4050 Author Contributions †
B.L. and A.L. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank Dr. Johannes C. Liermann (Mainz, NMR spectroscopy), Dr. Norbert Hanold (Mainz, deceased, mass spectrometry), Natalie Tober and Nico Röder (Mainz, technical advice), and the Carl Zeiss Foundation (project ChemBioMed, financial support).
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REFERENCES
(1) Liu, H.; Feng, M.; Jiang, X. Chem. - Asian J. 2014, 9, 3360. (2) (a) Jun, C.-H. Chem. Soc. Rev. 2004, 33, 610. (b) Chen, F.; Wang, T.; Jiao, N. Chem. Rev. 2014, 114, 8613. (c) Mondal, S.; Gold, B.; Mohamed, R. K.; Alabugin, I. V. Chem. - Eur. J. 2014, 20, 8664. (3) (a) Mella, M.; Freccero, M.; Fasani, E.; Albini, A. Chem. Soc. Rev. 1998, 27, 81. (b) Baciocchi, E.; Bietti, M.; Lanzalunga, O. J. Phys. Org. Chem. 2006, 19, 467. (4) Knabe, J.; Kubitz, J.; Ruppenthal, N. Angew. Chem., Int. Ed. Engl. 1963, 2, 689. (5) Langhals, E.; Langhals, H.; Rüchardt, C. Chem. Ber. 1984, 117, 1436. (6) Tauber, J.; Imbri, D.; Opatz, T. Molecules 2014, 19, 16190. (7) Blank, N.; Straub, B. F.; Opatz, T. Eur. J. Org. Chem. 2011, 2011, 7355. 2057
DOI: 10.1021/acs.orglett.7b00652 Org. Lett. 2017, 19, 2054−2057
