Letter Cite This: Org. Lett. 2018, 20, 1316−1319
pubs.acs.org/OrgLett
Vitamin Catalysis: Direct, Photocatalytic Synthesis of Benzocoumarins via (−)-Riboflavin-Mediated Electron Transfer Tobias Morack,† Jan B. Metternich,† and Ryan Gilmour* Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany S Supporting Information *
ABSTRACT: An operationally simple protocol is disclosed to facilitate entry to benzo-3,4-coumarins directly from biaryl carboxylic acids without the need for substrate prefunctionalization. Complementary to classic lactonization strategies, this disconnection relies on the oxidation competence of photoactivated (−)-riboflavin (vitamin B2) to generate the heterocyclic core via photoinduced single electron transfer. Collectively, the inexpensive nature of the catalyst, ease of execution, and absence of external metal additives are a convincing endorsement for the incorporation of simple vitamins in contemporary catalysis.
B
iomimetic chemistry endeavors to re-engineer Nature’s reactivity algorithms in a laboratory paradigm.1 These guiding principles manifest themselves heavily in modern organocatalysis,2 where most common activation modes have a biological foundation3 and can be emulated using low molecular weight organic catalysts.4 Often, these small molecules are commercially available, inexpensive, and nontoxic, and their synthetic application reflects their natural function. In particular, catalytically active vitamin derivatives underscore the value of biomimetic design. This aptitude for catalysis is particularly pronounced among the B-vitamin series.5 Synonymous with the burgeoning field of NHC catalysis, Breslow’s seminal investigations of the catalytic competence of vitamin B1 (thiamine)6 has evolved into a central pillar of contemporary, covalent organocatalysis. Since many vitamins also function as redoxactive cofactors in enzyme catalysis,7 they are ideally suited to emulate the mechanisms operational in photocatalysis.8 Indeed, their strategic application in light-activated processes might allow many common transformations to be executed in a more costeffective, metal-free manner. (−)-Riboflavin (vitamin B2) is a highly versatile organocatalyst for a variety of transformations:9 this is due to its inherent energy transfer (ET) and single electron transfer (SET) modes that can be activated upon irradiation.10 In this communication, the photoinduced electron transfer chemistry of (−)-riboflavin is assessed in the direct cyclization10b of biaryl carboxylic acids to form benzocoumarins. Since efficient catalyst regeneration only requires molecular oxygen, this strategy would mitigate any need for transition metals and/or additives. The benzo-3,4-coumarin (6H-benzo-[c]-chromene-6-one) structure is pervasive in translational research.11 It is common to a range of bioactive secondary metabolites with a diverse palette of bioactivities (Figure 1): pertinent examples include the © 2018 American Chemical Society
Figure 1. Examples of vitamin B catalysts that operate via both covalent (B1) and noncovalent (B2) activation modes.
antimalarial agent dioncolactone A (1), the antibacterials murayalactone (2) and chrysomysin A (3), the antifungal alternariol (4), and ellagic acid (5) which shows antiproliferative and antioxidant properties. The benzo-3,4-coumarin core is also conspicuous in the arena of organic photonics,12 where the structural tenacity of the lactone ensures that the planarity of the extended, delocalized π-systems is not compromised. This versatility spanning biomedicine through to smart materials has led many laboratories to intensively pursue efficient synthesis strategies to prepare the tricyclic lactone core by direct C(sp2)− H functionalization.13 To complement these existing methods, it was envisaged that the oxidation competence of photoactivated (−)-riboflavin might allow the benzo-3,4-coumarin to be generated directly from the corresponding biaryl carboxylic acid without the need for prefunctionalization. The blueprint for this investigation stemmed from the postulated biosynthesis of 4 Received: January 5, 2018 Published: February 15, 2018 1316
DOI: 10.1021/acs.orglett.8b00052 Org. Lett. 2018, 20, 1316−1319
Letter
Organic Letters
(−)-riboflavin to the substrate and is not limited to cinnamic acids.19 The subsequent oxidative lactonization engages the strong oxidizing properties of the activated photocatalyst8 to abstract an electron from the carboxylic acid, thereby inducing cyclization with the adjacent aromatic ring. Since effective cyclization is contingent on proximity of the carboxylic acid group to the aryl ring in the Z-isomer, the predefined spatial arrangement of the biaryl carboxlic acids in this study lends itself to this approach. Since the photophysical profiles of (−)-riboflavin and the biarylcarboxylic acid starting material were compatible, a preliminary optimization process was initiated (Table 1).
by Abe and co-workers, who noted that the noncyclized biaryl carboxylic acid (6) was produced by the same pathway from malonyl-CoA (Figure 2, center).14
Table 1. Reaction Optimizationa
entry
catalyst loading (%)
time (h)
atmosphere
solvent (MeOH/MeCN)
yield (%)
1 2 3 4 5 6 7 8 9 10 11 12 13
(2×) 5b 5 5 (2×) 5b (2×) 5b 10 10 (2×) 5b (2×) 5b (2×) 5b (2×) 5b 10 10
24 12 24 24 24 24 12 24 24 24 24 24 12
O2 O2 O2 air argon O2 O2 O2 O2 O2 O2 O2 O2
1:1 1:1 1:1 1:1 1:1 1:1 1:1 0:1 1:3 3:1 1:0 1:0 1:0
80 70 72 53 29 80 80 74 83 84 84 81 73
a
All reactions were carried out on a 0.1 mmol scale under UV-light irradiation at 402 nm at ambient temperature in 1.5 mL of solvent. b The second portion of catalyst was added after 12 h reaction time.
Reactions were conducted in MeOH/MeCN combinations and irradiated at 402 nm. Irradiation in a 1:1 MeOH/MeCN mixture for 24 h under an atmosphere of oxygen yielded the product in 80% yield (entry 1). To address partial photodecomposition, the initial catalyst loading was supplemented with an additional 5 mol % after each 12 h interval. Attempts to decrease the reaction time and catalyst loading (entries 2 and 3, respectively) diminished efficiency. Consistent with the initial hypothesis, the oxygen atmosphere was found to be critical to regenerate the active flavin. Reactions performed under air and argon atmospheres gave significantly lower yields (entries 4 and 5, 53 and 29%, respectively). Increasing the catalyst loading to 10 mol % did not influence the reaction outcome, with comparable efficiency having been observed after 12 and 24 h (entries 6 and 7). Slight variations in the solvent composition had little effect on performance (entries 8−11). Finally, direct addition of 10 mol % of (−)-riboflavin in MeOH with 12 h irradiation lowered the reaction efficiency. Consequently, the conditions employed in entry 11 with MeOH as the reaction medium were used for the remainder of the study. To establish the effect of structural modifications on this process, a variety of substrates were prepared and exposed to the standard conditions (Scheme 1). Introduction of parasubstituents on the A ring were generally well tolerated (10− 15, up to 84%). While the p-CF3 derivative (11) gave a moderate
Figure 2. Top: Selected benzocoumarin-containing natural products. Center: Postulated biosynthesis of the benzocoumarin alternariol and structural analogues.14 Bottom: Proposed strategy to access the benzocoumarin scaffold directly from the biarylcarboxylic acid using (−)-riboflavin and O2(g).
We speculated that a light-induced, oxidative cyclization mediated by an inexpensive, commercial vitamin would constitute a valuable addition to the benzocoumarin synthesis arsenal (Figure 2, bottom, 8 → 9). Confidence in this strategy was based on our previous biomimetic synthesis of coumarins directly from (E)-cinnamic acids.10 Emulating the phenyl propanoid biosynthesis pathway,15 it was possible to exploit the ET/SET modes of (−)-riboflavin to induce a sequential E → Z isomerization/cyclization process. In this cascade, (−)-riboflavin acts as a dual role photo-organocatalyst, promoting the E → Z isomerization of cinnamic acids in a first step.16−18 This process is based on the energy transfer from excited 1317
DOI: 10.1021/acs.orglett.8b00052 Org. Lett. 2018, 20, 1316−1319
Letter
Organic Letters Scheme 1. Oxidative Cyclization with (−)-Riboflavina
and 22 were synthesized. Both compounds were prepared in good yield (65 and 68% for 21 and 22, respectively). Finally, it was possible to access compound 20 in 40% yield directly from the pyridine-substituted benzoic acid. Mechanistically, it is proposed that singlet state electron transfer from benzoic acid to excited state (−)-riboflavin [E(3RF*/RF•−) = 1.46 V vs SCE] is operational (Scheme 2).20 This is based on an assumption of similar oxidation potentials of benzoic acid and cinnamic acid [E(S/S•−) = 1.30 V vs SCE).10 Scheme 2. Tentative Mechanistic Hypothesis
Based on our previous investigations, the catalytic cycle is likely initiated by protonation of (−)-riboflavin (RF) with strong absorption of the protonated flavin (see Scheme 2, RFH+) occurring at λmax = 402 nm. Subsequent single electron transfer from the carboxylate anion (I-1) to RFH+ yields the protonated flavin radical (RFH•) and the carboxy radical (I-2); this can undergo rapid cyclization to intermediate I-3. Final oxidation and rearomatization of I-3 with RFH• in a hydrogen atom transfer or SET/deprotonation reaction releases the product. The reduced (−)-riboflavin (RFH2) can, in turn, be reoxidized by molecular oxygen. However, oxidation of intermediate I-3 and RFH• by molecular oxygen cannot be discounted. In conclusion, a bioinspired oxidative lactonization of biaryl-2carboxylic acids is reported. Simple biphenyl-2-carboxylic acids can be converted directly to privileged benzo-3,4-coumarins with broad functional group tolerance. This includes challenging extended π-systems and a pyridine derivative, which are frequently incompatible with photochemical reaction conditions. Exploiting the photoinduced SET chemistry of (−)-riboflavin and the ability to oxidize the reduced flavin with molecular oxygen has generated a catalytic protocol that mitigates the need for metal catalysts and additives.
a
Reactions were carried out under an oxygen atmosphere (0.1 mmol scale) at ambient temperature in MeOH (1.5 mL). Catalyst loading of 5 mol % was used, and the reaction mixture was irradiated at 402 nm for the time indicated in parentheses. An additional 5 mol % of catalyst was added every 12 h.
yield of 45%, the corresponding p-Br (12) and p-F (13) derivatives were isolated in 69 and 72%, respectively. Importantly, the tolerance of the C(sp2)−Br bond in 12 to these conditions bodes well for subsequent structural modification. For the electron-deficient systems 11 and 13, it was necessary to extend the reaction time to 36 h. Finally, the p-tBu (14) and p-OCH3 (15) derivatives were prepared in 78 and 48%, respectively. In the course of exploring substituent effects on the B ring (16−20), fluorine incorporation delivered the highest yield of the study (16, 90%). Similar catalysis efficiency was found with substrates 17, 18, and 19 (p-Cl, p-CH3, and p-OCH3, 79, 73, and 76%, respectively). Interestingly, compound 20 proved to be more challenging, possibly due to increasing 1,3allylic strain in the course of the cyclization. Finally to provide preliminary validation of the method for the synthesis of extended π-conjugated systems for photonics, compounds 21
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00052. Experimental protocols and selected NMR spectra (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Ryan Gilmour: 0000-0002-3153-6065 1318
DOI: 10.1021/acs.orglett.8b00052 Org. Lett. 2018, 20, 1316−1319
Letter
Organic Letters Author Contributions
(k) Zhang, M.; Ruzi, R.; Li, N.; Zhu, C. Org. Chem. Front. 2018, DOI: 10.1039/C7QO00795G. (14) Sun, J.; Awakawa, T.; Noguchi, H.; Abe, I. Bioorg. Med. Chem. Lett. 2012, 22, 6397−6400. (15) Yao, R.; Zhao, Y.; Liu, T.; Huang, C.; Xu, S.; Sui, Z.; Luo, J.; Kong, L. Plant Mol. Biol. 2017, 95, 199−213. (16) Metternich, J. B.; Gilmour, R. J. Am. Chem. Soc. 2015, 137, 11254−11257. (17) Singh, K.; Staig, S. J.; Weaver, J. D. J. Am. Chem. Soc. 2014, 136, 5275−5278. (18) For a review, see: Metternich, J. B.; Gilmour, R. Synlett 2016, 27, 2541−2552. (19) Metternich, J. B.; Artiukhin, D. G.; Holland, M. C.; von BremenKühne, M.; Neugebauer, J.; Gilmour, R. J. Org. Chem. 2017, 82, 9955− 9977. (20) Lu, C.-Y.; Wang, W.-F.; Lin, W.-Z.; Han, Z.-H.; Yao, S.-D.; Lin, N.-Y. J. Photochem. Photobiol., B 1999, 52, 111−116.
†
T.M. and J.B.M. contributed equally to this work.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS We acknowledge financial support from the WWU Münster, Deutsche Forschungsgemeinschaft (Excellence Cluster EXC 1003), Studienstiftung des deutschen Volkes (Fellowship to T.M.) and the Fonds der Chemischen Industrie (Fellowship to J.B.M.).
■
REFERENCES
(1) (a) Breslow, R. Chem. Soc. Rev. 1972, 1, 553−580. (b) Breslow, R. Acc. Chem. Res. 1995, 28, 146−1153. (2) Asymmetric Organocatalysis: From Biomimetic Concepts to Applications in Asymmetric Synthesis; Berkessel, A., Gröger, H., Eds.; Wiley-VCH: Weinheim, 2005. (3) Knowles, R. R.; Jacobsen, E. N. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 20678−2068. (4) Holland, M. C.; Gilmour, R. Angew. Chem., Int. Ed. 2015, 54, 3862− 3871. (5) (a) Brown, K. L. Chem. Rev. 2005, 105, 2075−2150. (b) Giedyk, M.; Goliszewska, K.; Gryko, D. Chem. Soc. Rev. 2015, 44, 3391−3404. (6) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719−3726. (7) Redox Biochemistry; Banerjee, R., Becker, D. F., Dickman, M. B., Gladyshev, V. N., Ragsdale, S. W., Eds.; Wiley-VCH: Weinheim, 2007. (8) (a) Turro, N. J.; Ramamurthy, V.; Scaiano, J. C. Modern Molecular Photochemistry of Organic Molecules; University Science Books: Sausalito, CA, 2010. For recent reviews on photocatalysis, see: (b) Yoon, T. P.; Ischay, M. A.; Du, J. Nat. Chem. 2010, 2, 527−532. (c) Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40, 102−113. (d) Xuan, J.; Xiao, W. Angew. Chem., Int. Ed. 2012, 51, 6828− 6838. (e) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322−53263. (f) Schultz, D. M.; Yoon, T. P. Science 2014, 343, 1239176. (g) Nicewicz, D. A.; Nguyen, T. M. ACS Catal. 2014, 4, 355. (h) Brimioulle, R.; Lenhart, D.; Maturi, M. M.; Bach, T. Angew. Chem., Int. Ed. 2015, 54, 3872−3890. (i) Romero, N. A.; Nicewicz, D. A. Chem. Rev. 2016, 116, 10075−10166. (9) Massey, V. Biochem. Soc. Trans. 2000, 28, 283−296. (10) (a) Metternich, J. B.; Gilmour, R. J. Am. Chem. Soc. 2016, 138, 1040−1045. (b) For a review on cyclization induced by SET, see: Plesniak, M. P.; Huang, H.-M.; Procter, D. J. Nature Rev. Chem. 2017, 1, 0077. (11) (a) Edwards, K. G.; Stoker, J. R. Phytochemistry 1967, 6, 655−661. (b) Murray, R. D. H.; Mendez, J.; Brown, S. A. The Natural Coumarins: Occurrence, Chemistry, and Biochemistry; Wiley: New York, 1982. (c) Matern, U.; Lüerm, P.; Kreusch, D. Biosynthesis of Coumarins. In Comprehensive Natural Product Chemistry:Polyketides and Other Secondary Metabolites; Sankawa, U., Ed.; Pergamon: Oxford, UK, 1999; Vol. 1. (12) Tasior, M.; Kim, D.; Singha, S.; Krzeszewski, M.; Ahn, K. H.; Gryko, D. T. J. Mater. Chem. C 2015, 3, 1421−1446. (13) For selected examples, see: (a) Kenner, G. W.; Murray, M. A.; Tylor, C. M. B. Tetrahedron 1957, 1, 259−268. (b) Davies, D. I.; Waring, C. Chem. Commun. 1965, 263−264. (c) Togo, H.; Muraki, T.; Yokoyama, M. Tetrahedron Lett. 1995, 36, 7089−7092. (d) Li, Y.; Ding, Y.-J.; Wang, J.-Y.; Su, Y.-M.; Wang, X.-S. Org. Lett. 2013, 15, 2574−2577. (e) Wang, Y.; Gulevich, A. V.; Gevorgyan, V. Chem. - Eur. J. 2013, 19, 15836−15840. (f) Gallardo-Donaire, J.; Martin, R. J. Am. Chem. Soc. 2013, 135, 9350−9353. (g) Dai, J.-J.; Xu, W.-T.; Wu, Y.-D.; Zhang, W.-M.; Gong, Y.; He, X.-P.; Zhang, X.-Q.; Xu, H. J. J. Org. Chem. 2015, 80, 911−919. (h) Ramirez, N. P.; Bosque, I.; Gonzalez-Gomez, J. C. Org. Lett. 2015, 17, 4550−4553. (i) Zhang, S.; Li, L.; Wang, H.; Li, Q.; Liu, W.; Xu, K.; Zeng, C. Org. Lett. 2018, 20, 252−255. (j) Yang, Q.; Jia, Z.; Li, L.; Zhang, L.; Luo, S. Org. Chem. Front. 2018, 5, 237−241. 1319
DOI: 10.1021/acs.orglett.8b00052 Org. Lett. 2018, 20, 1316−1319
