No photocatalyst required – versatile, visible light mediated transformations with polyhalomethanes

Abstract

A visible light mediated, but photocatalyst-free method for the oxidative α-CH functionalization of tertiary amines with a broad scope of carbon- and heteroatom nucleophiles using polyhalomethanes has been developed. In addition, the pivotal visible light triggered activation of polyhalomethanes offers mild conditions for efficient Kharasch-type additions onto non-activated olefins. Preliminary mechanistic studies are reported.

---

Visible light photocatalysis has recently emerged as a versatile strategy for challenging C–H activation reactions of sp³-hybridized carbon atoms allowing for the direct and selective construction of C–X and C–C bonds without the need of substrate pre-activation.¹ The use of photoredox catalysis for the facile generation of reactive intermediates, such as iminium ions² or α-amino radicals³ from tertiary amines⁴ is highly attractive due to the mild conditions and hence its potential compatibility for multicatalytic processes.⁵ As an alternative to cross dehydrogenative coupling reactions (CDC),⁶ which are generally either metal-catalyzed or mediated by organic oxidants, a multitude of novel methods employing different photocatalysts have been established.⁷ Using the CDC activation of tetrahydroisoquinolines (THIQ) as a benchmark reaction typical photocatalysts range from organometallic complexes⁸ (mostly Ru²⁺ and Ir³⁺ based) and simple organic dyes⁹ to MOFs, graphene oxides as well as organic and inorganic semiconductors.¹⁰ Dual catalysis involving photocatalysis,¹¹ which allows access to unprecedented transformations by a beneficial combination of the concurrent catalytic generation of both electrophile and nucleophile, has been developed for metal and organocatalytic activation modes. In the context of THIQ iminium derivatives as electrophiles the nucleophilic catalytic intermediates have been formed via metal catalysis^12,13 as well as via covalent^14–16 and non-covalent organocatalysis including highly enantioselective approaches to β-amino acid esters¹⁷ and α-acylated tertiary amines¹⁸ or propargylic amines.^12b

In the context of our own interest in novel synergistic and cooperative catalytic activation modes combining organocatalysis with photoredox catalysis,¹⁹ we also investigated the photocatalytic approach to iminium ion precursors from tertiary amines, namely THIQs. Apart from the great number of metal and organocatalyzed oxidative processes, two major groups of photocatalytic methods have been described: aerobic techniques in the presence of air or O₂ and procedures which rely on the addition of external oxidants, such as alkyl halogenides (bromomalonate, BrCCl₃etc.)²⁰ or nitro compounds^2,18 to regenerate the photocatalyst (Scheme 1). With respect to the above mentioned required compatibility to potentially unstable nucleophilic catalytic intermediates we decided to focus on methods with external oxidants to avoid detrimental interactions of reactive oxygen intermediates such as superoxide radical anions or peroxides.²¹

Scheme 1 Iminium ions: access strategies and applications.

Based on the well-documented weak C–Hal bonds in polyhalomethanes (low bond dissociation energies (BDEs), e.g. Br–CCl₃: 55.3 kcal mol⁻¹),²² being in the energy range accessible by visible light together with the established ability of CCl₃˙ radicals to serve as acceptors in hydrogen atom transfer reactions (HAT), we questioned whether these prerequisites would allow a direct, photocatalyst-free, visible light mediated access to iminium intermediates from tertiary amines.²³ With respect to BDEs the trichloromethyl radical (H–CCl₃ BDE ≈ 95 kcal mol⁻¹) should readily abstract a hydrogen atom from amine substrates (α-C–H BDE ≈ 84–90 kcal mol⁻¹)²² to generate α-amino radicals and subsequently the crucial iminium ions upon either an electron or atom transfer pathway. We hoped to provide an alternative to the oxidation-potential-gated methods and hence to introduce a highly practical general pathway to a C–H functionalization using visible light as sole driving force for substrate partners with weak C–H bonds. Moreover, we anticipated that such a strategy would be ideally suited for multicatalytic transformations and the implementation of substrates that might form detrimental by-products via undesired photocatalytic processes.²⁴ Herein we describe the successful realization of this proposal and present preliminary studies providing insights to the mechanism.

As outlined in Table 1 we started our search for the best conditions with the direct transformation of N-phenyl THIQ 1 to its corresponding iminium salt 2. An initial evaluation of the reagent CBrCl₃ revealed that stochiometric amounts seemed to be sufficient, however a small excess (Table 1, entry 4) ensured a cleaner reaction within a shorter time frame. Similar results could be obtained by irradiation with a household compact fluorescent light bulb or sunlight (entries 5, 6). For the successful transformation to the iminium salt the presence of light proved to be essential; lower energy light sources, such as green light were not sufficient (entries 7, 8). The thermal reaction²⁵ in acetonitrile at 70 °C or 100 °C using toluene as solvent (decomposition) was not competitive.²⁶ Employment of less activated CCl₄ (Cl–CCl₃ BDE = 70.9 kcal mol⁻¹;²²λ_corr ≈ 404 nm) still allows completion of the reaction using our standard conditions, however with a strongly increased reaction time.²⁶

Table 1 Transformation of THIQ 1 to its iminium salt – initial studies and reaction optimization^a

Entry	Equiv. of CBrCl3	Light source	Temperature	Reaction time^b	Yield^c (%)
a 0.25 mmol of THIQ in 0.5 mL acetonitrile, x mmol of CBrCl3 as noted. b In min. c Determined by ^1H NMR spectroscopy using bromoform (1 equiv.) as internal standard. d Large scale experiment using 2.5 mmol of THIQ.
1	3.0	Blue LEDs	rt	30	91
2	1.0	Blue LEDs	rt	30	97
3	1.0	Blue LEDs	rt	60	99
4	1.5	Blue LEDs	rt	30	Quant.
5	1.5	22 W CWF bulb	rt	30	Quant.
6	1.5	Sunlight	rt	30	91
7	1.5	No light	70 °C	30	23
8	1.5	Green LEDs	rt	30	14
9^d	1.5	Blue LEDs	rt	30	95

---

An additional comprehensive survey on solvent effects²⁶ demonstrated the robustness of this transformation. The reaction could be successfully conducted in organic solvents ranging from less polar ethers, halogenated solvents and alkanes to more polar alcohols, but also in water. Having established our best conditions we examined the scope of different THIQs in this transformation: both electron-poor and electron-rich substrates allowed for an efficient generation of their corresponding iminium ions (Fig. 1).²⁷ Notably, our protocol also allows transformations of N-alkyl THIQs to their corresponding iminium salts 6 and 7, which have only scarcely been applied²⁸ in visible light photoredox catalyses due to their higher oxidation potential.²⁹ Employment of N-acyl THIQ substrates with further increased oxidation potential^29c leads to highly reactive N-acyliminium salts³⁰ which cannot be isolated. However, C–H activation of these substrates (for a further example, see transformation of dimethylformamide (DMF) in Fig. 3) was proven by isolation of their corresponding by-products, such as a cyclized derivative stemming from the corresponding Boc-protected THIQ.²⁶

Fig. 1 Visible light assisted generation of iminium ions from N-aryl and N-alkyl THIQs (yields determined by NMR using CH₂Br₂ or CHBr₃ as internal standard).

Next we checked the applicability of our conditions for subsequent C–C and C–X cross coupling reactions. We examined literature known nucleophiles which were directly added to the reaction mixture after irradiation with blue light.^9a,12,15,20 Both phosphorous and carbon nucleophiles reacted smoothly with the pregenerated iminium salt in a sequential one-pot fashion and without further manipulation of the reaction conditions required (Fig. 2A). Apart from C–H-acidic nitromethane (aza-Henry reaction) and malonate providing excellent yields, electron-rich indole proved to be a competent substrate for the corresponding arylation reaction. Next we focused on expanding the method to multicatalytic processes. As outlined in Fig. 2B our method is applicable to both metal and organocatalytic in situ generation of nucleophiles. Cu-catalyzed alkynylation^12,20 proceeds in excellent yield and Lewis-base catalyzed Morita–Baylis–Hillman¹⁵ reaction affords the acroleinated THIQ 12 in good yield. All reactions are easily handled and provide similar yields to the related transformations using an additional photocatalyst.

Fig. 2 Cross coupling reactions of iminium bromide salts with carbon and heteroatom nucleophiles (yields determined by NMR using CH₂Br₂ as internal standard, isolated yields*).

Fig. 3 Cross coupling with potassium styryl trifluoroborate (yields determined by NMR using CH₂Br₂ as internal standard).

In addition, we could extend the scope of C-nucleophiles to trifluoroborate salts which are also competent reaction partners. This is perhaps most remarkable as photocatalytic pathways either using aerobic conditions (e.g. with Ru or xanthene dyes as photocatalysts where occurring oxygen species²¹ may contribute to the decomposition of trifluoroborate 14)³¹ or with external oxidants were not equally successful for providing the corresponding vinylation product in a sequential one-pot fashion (best yield: 58%). This is most probably connected with a detrimental interaction of the substrate with remaining catalyst-derived species. Interestingly, as noticed in a control reaction to prove potential side reactions, DMF can also undergo styrenylation under similar conditions, albeit in low yield only (not optimized²⁶).

At this stage we undertook an in situ IR tracing of the standard THIQ reaction to gain further mechanistic insights (Fig. 4). This experiment clearly reveals the fast and clean transformation of the THIQ starting material 1 to its corresponding iminium salt 2 in approx. 8 min according to the indicative vibrational bands at 1604 cm⁻¹ (THIQ 1) and 1640 cm⁻¹ for developing iminium salt 2.

Fig. 4 In situ IR-reaction monitoring of visible light-assisted generation of THIQ iminium ion 2 from THIQ 1 with CBrCl₃.

Further control experiments with short periods of irradiation and subsequent dark periods resulted in interruption of the reaction progress in the absence of light and recovery of the former reactivity upon further illumination, hence demonstrating the light dependence of the reactions. This suggests that, if a radical chain mechanism is operative, the corresponding chain might only be very short as only during irradiation periods significant reaction progress is observed.²⁶ To additionally exclude a possible involvement of UV light we irradiated the sample through a UV filter (75% w/v NaNO₂ solution, cut-off: λ = 400 nm).²⁶ No differences in yield and performance for the formation of the iminium bromide 2 were observed. Based on the observation of a short-lived, intense blue coloration of the THIQ solution containing CBrCl₃ upon irradiation,²⁶ the participation of a redox pathway via the known formation of amine polyhalomethane electron donor acceptor (EDA) complexes³² might be operative. However, due to the aforementioned low BDE of C–Br bonds and the observed positive results in transforming of substrates with higher oxidation potentials, we questioned whether this reaction is solely promoted by the formation of an EDA complex. Based on both cyclovoltammetric measurements and a series of KI/starch tests²⁶ we can exclude a direct oxidation or the presence of an oxidant before irradiation; in addition, blue light irradition of CBrCl₃ alone showed a positive KI/starch test. Hence, we additionally suggest an initial homolytic bond fission to yield a bromine and a trichloromethyl radical (see Scheme 2A) as a second, alternative pathway. To validate our preliminary mechanistic picture, we performed a Kharasch reaction (Fig. 5), i.e. the ATRA reaction of a polyhalomethane to non-activated alkenes.^33,34 Typical ATRA initiations such as radical starters, Lewis acids or by high temperature or UV light have recently been supplemented by a number of photoredox catalytic transformations (using Ru, Ir and Cu based catalysts).^35,36 Using a similar set-up as optimized for the THIQ transformations we could access the addition product 18 of the ω-hydroxy alkene 17 in excellent yield and selectivity comparable to catalyst mediated processes, however under remarkably mild conditions.

Scheme 2 Mechanistic considerations.

Fig. 5 Kharasch addition of CBrCl₃ with visible light.

Scheme 2 summarizes our preliminary mechanistic picture. Besides an involvement of EDA complexes in terms of amine substrates (Scheme 2B), whose excitation facilitates charge transfer to generate both the amino radical cation and an instable CBrCl₃ radical anion, a number of different mechanistic pathways are conceivable upon light-mediated fission of CBrCl₃, namely both a redox pathway where the bromine radical generates the common amino radical cation, while the other routes builds on hydrogen atom transfers as crucial steps. The fact that we could also observe the formation of chloroform,²⁶ also points to the important involvement of CCl₃˙ radicals in HAT steps as hydrogen acceptor.

With respect to the BDEs the trichloromethyl radical (H–CCl₃ BDE ≈ 95 kcal mol⁻¹) should readily abstract a hydrogen atom from amine substrates (α-C–H BDE ≈ 84–90 kcal mol⁻¹),²² but similarly a bromine radical (H–Br BDE ≈ 88 kcal mol⁻¹) could still be able to trigger the formation of the central α-amino radical which might undergo numerous pathways towards the iminium ion 2.

In conclusion, we have demonstrated the applicability of visible (blue) light for the activation of polyhalomethanes in a broad range of different reactions. CDC coupling of THIQs as well as Kharasch-type addition reactions to olefins were achieved in good to excellent yields. As the light-assisted α-C–H activation of amines does not only rely on redox properties, but rather on suitably low BDEs of the corresponding C–H bonds, we expect this mild, metal-free and operational simple method to not only provide a valuable alternative to established catalyst-promoted procedures, especially in the context of dual or multicatalytic reactions, but also to be broader applicable for currently unattainable transformations. More detailed mechanistic studies are currently in progress.

Financial support from the DBU (fellowship to J. F. Franz) and the DFG (GRK 1626) is gratefully acknowledged. We also thank J. A. Allen and O. Jaurich (Mettler TOLEDO) for their support.

Notes and references

1. For recent reviews, see: (a) C. K. Prier, D. A. Rankic and D. W. C. MacMillan, Chem. Rev., 2013, 113, 5322; (b) D. M. Schultz and T. P. Yoon, Science, 2014, 343, 1239176; (c) K. Zeitler, Angew. Chem., Int. Ed., 2009, 48, 9785.
2. For a seminal example, see: A. G. Condie, J.-C. González-Gómez and C. R. J. Stephenson, J. Am. Chem. Soc., 2010, 132, 1464.
3. For seminal examples, see: (a) P. Kohls, D. Jadhav, G. Pandey and O. Reiser, Org. Lett., 2012, 14, 672; (b) Y. Miyake, K. Nakajima and Y. Nishibayashi, J. Am. Chem. Soc., 2012, 134, 3338.
4. For a recent review on photocatalytic α-functionalization of amines, see: L. Shi and W. Xia, Chem. Soc. Rev., 2012, 41, 7687.
5. For recent reviews, see: (a) R. C. Wende and P. R. Schreiner, Green Chem., 2012, 14, 1821; (b) A. E. Allen and D. W. C. MacMillan, Chem. Sci., 2012, 3, 633.
6. For a recent update, see: S. A. Girard, T. Knauber and C.-J. Li, Angew. Chem., Int. Ed., 2014, 53, 74.
7. For an instructive review, see: L. Furst and C. R. J. Stephenson, in Carbon–carbon Bond Formations via Cross-Dehydrogenative-Coupling of C–H Bonds, ed. C.-J. Li, Royal Society of Chemistry, Cambridge, 2015.
8. (a) G. Zhao, C. Yang, L. Guo, H. Sun, C. Chen and W. Xia, Chem. Commun., 2012, 48, 2337; (b) M. Rueping, S. Zhu and R. M. Koenigs, Chem. Commun., 2011, 47, 12709; (c) J.-J. Zhong, Q.-Y. Meng, G.-X. Wang, Q. Liu, B. Chen, K. Feng, C.-H. Tung and L.-Z. Wu, Chem. – Eur. J., 2013, 19, 6443.
9. (a) D. P. Hari and B. König, Org. Lett., 2011, 13, 3852; (b) Y. Pan, C. W. Kee, L. Chen and C.-H. Tan, Green Chem., 2011, 13, 2682.
10. (a) M. Rueping, J. Zoller, D. C. Fabry, K. Poscharny, R. M. Koenigs, T. E. Weirich and J. Mayer, Chem. – Eur. J., 2012, 18, 3478; (b) L. Möhlmann and S. Blechert, Adv. Synth. Catal., 2014, 356, 2825.
11. (a) M. Neumann and K. Zeitler, in Chemical Photocatalysis, ed. B. König, de Gruyter, 2013; for two recent examples, see: (b) J. C. Tellis, D. N. Primer and G. A. Molander, Science, 2014, 345, 433; (c) Z. Zuo, D. Ahneman, L. Chu, J. Terrett, A. G. Doyle and D. W. C. MacMillan, Science, 2014, 345, 437.
12. (a) M. Rueping, R. M. Koenigs, K. Poscharny, D. C. Fabry, D. Leonori and C. Vila, Chem. – Eur. J., 2012, 18, 5170; (b) I. Perepichka, S. Kundu, Z. Hearne and C.-J. Li, Org. Biomol. Chem., 2015, 13, 447.
13. J.-J. Zhong, Q.-Y. Meng, B. Liu, X.-B. Li, X.-W. Gao, T. Lei, C.-J. Wu, Z.-J. Li, C.-H. Tung and L.-Z. Wu, Org. Lett., 2014, 16, 1988.
14. M. Rueping, C. Vila, R. M. Koenigs, K. Poscharny and D. Fabry, Chem. Commun., 2011, 47, 2360.
15. Z.-J. Feng, J. Xuan, X.-D. Xia, W. Ding, W. Guo, J.-R. Chen, Y.-Q. Zou, L.-Q. Lu and W.-J. Xiao, Org. Biomol. Chem., 2014, 12, 2037.
16. W. Li, X. Zhu, H. Mao, Z. Tang, Y. Chenga and C. Zhu, Chem. Commun., 2014, 50, 7521.
17. G. Bergonzini, C. S. Schindler, C.-J. Wallentin, E. N. Jacobsen and C. R. J. Stephenson, Chem. Sci., 2014, 5, 112.
18. D. A. DiRocco and T. Rovis, J. Am. Chem. Soc., 2012, 134, 8094.
19. (a) M. Neumann, S. Füldner, B. König and K. Zeitler, Angew. Chem., Int. Ed., 2011, 50, 951; (b) M. Neumann and K. Zeitler, Org. Lett., 2012, 14, 2658; (c) M. Neumann and K. Zeitler, Chem. – Eur. J., 2013, 19, 6950.
20. D. B. Freeman, L. Furst, A. G. Condie and C. R. J. Stephenson, Org. Lett., 2012, 14, 94.
21. Q. Liu, Y.-N. Li, H.-H. Zhang, B. Chen, C.-H. Tung and L.-Z. Wu, Chem. – Eur. J., 2012, 18, 620.
22. Y.-R. Luo, Comprehensive Handbook of Chemical Bond Energies, CRC Press, Boca Raton, 2007.
23. For a selection of recently published examples of catalyst-free transformations with visible light: (a) I. D. Arceo, A. Jurberg, A. Álvarez-Fernàndez and P. Melchiorre, Nat. Chem., 2013, 5, 750; (b) H. Jiang, J. R. Bak, F. J. López-Delgado and K. A. Jørgensen, Green Chem., 2013, 15, 3355; (c) E. Arceo, A. Bahamonde, G. Bergonzini and P. Melchiorre, Chem. Sci., 2014, 5, 2438; (d) E. Arceo, E. Montroni and P. Melchiorre, Angew. Chem., Int. Ed., 2014, 53, 12064; (e) M. Tobisu, T. Furukawa and N. Chatani, Chem. Lett., 2013, 42, 1203.
24. The frequent use of various Ir catalysts for CDC reactions can e.g. trigger undesired dehalogenations of aromatic bromides: (a) J. D. Nguyen, E. M. D'Amato, J. M. R. Narayanam and C. R. J. Stephenson, Nat. Chem., 2012, 4, 854; (b) H. Kim and C. Lee, Angew. Chem., Int. Ed., 2012, 51, 12303 ; for reported diminished yields, see ref. 12b. Carboxylic acid and trifluoroborate substrates might also suffer from the strong oxidation potential of Ir photocatalysts: see ref. 11b and c.
25. (a) C. Dai, F. Meschini, J. M. R. Narayanam and C. R. J. Stephenson, J. Org. Chem., 2012, 77, 4425; (b) H. Ueda, K. Yoshida and H. Tokuyama, Org. Lett., 2014, 16, 4194.
26. See ESI† for details.
27. For the X-ray structure of iminium salt 2, please refer to ESI.† CCDC 993641.
28. W. Fu, W. Guo, G. Zou and C. Xu, J. Fluorine Chem., 2012, 140, 88.
29. For comparison: redox potential (all given vs. SCE) of (a) N-Ph-THIQ: 0.84 V, see ref. 25a; (b) N-Et-THIQ: 1.20 V, see: G. Pandey, K. S. Rani and G. Lakshmaiah, Tetrahedron Lett., 1992, 33, 5107; (c) tertiary carbamates: 1.50–1.90 V, L. Haya, F. J. Sayago, A. M. Mainar, C. Cativiela and J. S. Urieta, Phys. Chem. Chem. Phys., 2011, 13, 17696.
30. B. E. Maryanoff, H.-C. Zhang, J. H. Cohen, I. J. Turchi and C. A. Maryanoff, Chem. Rev., 2004, 104, 1431.
31. For the intended photocatalytically induced oxidation of less stable boronic acids, see: (a) Y.-Q. Zou, J.-R. Chen, X.-P. Liu, L.-Q. Lu, R. L. Davis, K. A. Jørgensen and W.-J. Xiao, Angew. Chem., Int. Ed., 2012, 51, 784; (b) S. P. Pitre, C. D. McTiernan, H. Ismaili and J. C. Scaiano, J. Am. Chem. Soc., 2013, 135, 13286.
32. (a) L. Eberson and M. Ekström, Acta Chem. Scand., 1989, 43, 86; (b) D. P. Stevenson and G. M. Coppinger, J. Am. Chem. Soc., 1986, 84, 149.
33. (a) M. S. Kharasch, E. V. Jensen and W. H. Urry, Science, 1945, 102, 128; (b) M. S. Kharasch, E. V. Jensen and W. H. Urry, J. Am. Chem. Soc., 1946, 68, 154.
34. During the blue light irradiation of alkene 17 with CBrCl₃ we did not observe any coloration of the reaction mixture; see ESI† for details.
35. (a) C.-J. Wallentin, J. D. Nguyen, P. Finkbeiner and C. R. J. Stephenson, J. Am. Chem. Soc., 2012, 134, 8875; (b) M. Pirtsch, S. Paria, T. Matsuno, H. Isobe and O. Reiser, Chem. – Eur. J., 2012, 18, 733.
36. For a recent metal-free approach using aromatic aldehydes as energy transfer sensitizer, see: ref. 23d.

---

Footnote

† Electronic supplementary information (ESI) available: Full experimental details and characterization. CCDC 993641. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc10270c

---