Letter Cite This: Org. Lett. 2018, 20, 724−727
pubs.acs.org/OrgLett
Spatiotemporal Control of Pre-existing Alkene Geometry: A BioInspired Route to 4‑Trifluoromethyl‑2H‑chromenes Svenja I. Faßbender,† Jan B. Metternich,† and Ryan Gilmour* Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstr. 40, 48149 Münster, Germany S Supporting Information *
ABSTRACT: Routes to prepare C4-trifluoromethyl analogues of the 2H-chromene scaffold are scarce: this is particularly striking given the importance of fluorine in pharmaceutical development. To address this limitation, a facile strategy has been developed that is reliant on catalytic, geometric isomerization of easily accessible allylic alcohols (up to >95:5) followed by intramolecular cyclization via Pd catalysis (up to 96%). This concise biomimetic approach emulates the photoisomerization/cyclization cascade inherent to phenylpropanoid biosynthesis.
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patiotemporal control of pre-existing alkene geometry is a challenging problem in organic synthesis, particularly when the efficiency of subsequent transformations is predicated on a predefined configuration.1 An amalgamation of thermodynamics and microscopic reversibility further compounds this problem, resulting in a general deficiency in the synthetic arsenal for this fundamental transformation. Unlike positional isomerization,2 there is a conspicuous absence of general catalysts to affect geometric isomerization in a specific direction.3 However, the current renaissance of organic photochemistry provides a platform for development of efficient methods to facilitate selective alkene isomerization at a defined stage of a synthetic sequence: light-induced spatiotemporal control.4 This is attributable to the initial excitation process that circumvents the principle of microscopic reversibility5 and ensures that the subsequent reaction coordinate is energetically downhill. Seminal mechanistic insights into photocatalytic alkene isomerization of styrenes and stilbenes6−8 provide expansive blueprints from which to develop synthetically powerful methods. While the direct excitation of alkenes is possible, photosensitization using a small-molecule catalyst is often more efficient and allows for selective activation of a specific functional group. This strategy has been effectively demonstrated using an Ir(III) complex9 and by this laboratory using (−)-riboflavin to expedite the E→Z isomerization of activated olefins via an energy transfer manifold.10 In this latter case, initial isomerization can be coupled to a second step exploiting photoinduced single-electron transfer to oxidatively cyclize cinnamic acids directly to coumarins.11 This process mimics the initial stage of coumarin biosynthesis via the phenylpropanoid pathway.12 Because sequential isomerization/cyclization processes are pervasive in Nature (Figure 1, top),13 it was envisaged that a photocatalytic isomerization approach may facilitate biomimetic synthesis of a structurally related 2H-chromene scaffold. This motif constitutes the core of a plethora of bioactive natural products and pharmaceuticals (Figure 1, bottom), thus development of concise synthetic routes has been intensely pursued.14 © 2018 American Chemical Society
Figure 1. General, biomimetic strategy based on coumarin biosynthesis and selected natural 2H-chromene derivatives.
To validate this biomimetic strategy, 4-trifluoromethylated analogs were identified as being of particular interest due to the prominence of fluorine in bioactive molecule design (Figure 2).15 A structure search revealed that relatively few examples of CF3-containing 2H-chromenes have been reported;16 this is in stark contrast with the corresponding 4-Et scaffold which Received: December 11, 2017 Published: January 16, 2018 724
DOI: 10.1021/acs.orglett.7b03859 Org. Lett. 2018, 20, 724−727
Letter
Organic Letters
Figure 3. Reaction progress monitoring of Z-1 to E-1 by HPLC using a CHIRACEL OJ H column, hexane/iPrOH = 90:10, 0.5 mL·min−1; tR(Z1) = 10.2 min, tR(E-1) = 22.1 min.
alcohols19 suggested that H to CF3 substitution may be advantageous in suppressing this reactivity. From the reaction design perspective, intrinsic directionality [Z-1→E-1] would be conditional on a selective excitation manifold (Figure 2, bottom). As the starting Z-allylic alcohol is planar, it would differ in excitation efficiency from that of the product E-allylic alcohol. This is due to 1,3-allylic strain20 in the product distorting the πsystem and reducing conjugation. The consequence is that Z-1 can be excited to the postulated diradical intermediate,10a which can collapse to the starting material or product. Because the reverse reaction is inefficient due to the loss of conjugation in the chromophore, high selectivity for E-1 is expected. As triplet energy transfer (ET) was expected to be operational in the initial isomerization, common sensitizers were systematically explored under irradiation at 365 or 450 nm (Table 1, Z-1→E-1). Reactions were performed in the solvent indicated for 24 h. Benzophenone (entry 2) and anthracene (entry 6) were identified as being highly efficient (94:6 and >95:5, respectively). Based on considerations of cost and simplicity, the study was advanced using anthracene (Sigma-Aldrich, 100 g = $55.50). Acetonitrile was an excellent reaction medium, and catalyst loadings as low as 2 mol % continued to deliver excellent Z/E ratios (>95:5) as determined by 1H NMR analysis of the crude mixture (entry 9). Ir(ppy)3 featured prominently in the study by Weaver9 was ineffective in the isomerization of Z-1, proving a degree of complementarity to these studies.
Figure 2. Top: Sci-Finder hits for the three chromene systems indicated (performed 11/30/2017). Center: A conceptual overview of this study. Bottom: Design principles employed in the initial isomerization.
provides a useful benchmark due to similar steric volumes of CF3 and Et (39.8 and 38.9 Å3, respectively) (Figure 2, top).17 A twostep sequence reliant on the efficient isomerization of an easily prepared Z-configured allylic alcohol,18 and concomitant cyclization, provides facile access to 4-CF3 2H-chromenes. Selective excitation of the planar starting material would be ensured due to 1,3-allylic strain that would manifest itself in the twisted, deconjugated chromophore of the product. This would endow the reaction with an intrinsic directionality. While this was sufficient impetus for reaction development, a study describing the photosensitized degradation of cinnamyl Table 1. Optimization of the Photocatalytic Isomerization
entry 1 2 3 4 5 6 7 8 9
catalyst benzophenone Ir(ppy)3 fluorenone eosin Y anthracene Rose Bengal methylene blue anthracene
ET (kJ/mol) 286.6 235.6 223.0 190.3 178.6 170.8 144.7 178.6
catalyst loading (mol %)
solvent
scale (mmol)
E/Zc ratio
5 5 5 5 5 5 5 2
MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN
0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1
0:100a 94:6a 95:5 2/1), but the efficiency of the transformation was heavily
dependent on the nature of R1. Only a 50% material recovery was recorded in the case of 2d, R1 = Et, whereas the corresponding CF3 derivative 2c was processed quantitatively. The p-OCH3 derivatives (1e and 1f) were markedly different in their isomerization efficiency and selectivity (R1 = CF3, quant., 2e/ 1e >95:5 vs R1 = Et, yield and E/Z ratio not determined due to degradation). This variance in yield between R1 = Et and R1 = CF3 persisted throughout the series with the p-Me (1g vs 1h), pCl (1i vs 1j), and p-F (1k vs 1l) substituted derivatives giving similar E/Z ratios but markedly different yields (Δ up to 50%). This supports the notion that the CF3 group occupies a comparable steric volume to Et, which influences selectivity.10b Degradative photochemical pathways that plague the carbogenic scaffolds are suppressed by the CF3 group. Due to the importance of the difluoromethyl group as an effective hydrogen bond donor in structural and medicinal chemistry,21 we explored a model substrate in which R1 = CHF2 (Scheme 2). Isomerization was highly selective (E/Z >95:5) with 89% yield. With an optimized set of isomerization conditions to 726
DOI: 10.1021/acs.orglett.7b03859 Org. Lett. 2018, 20, 724−727
Letter
Organic Letters
L.-G.; Yao, Z.-K.; Yu, Z.-X. Org. Lett. 2013, 15, 4634. (c) Chen, C.; Dugan, T. R.; Brennessel, W. W.; Weix, D. J.; Holland, P. L. J. Am. Chem. Soc. 2014, 136, 945. (d) Timsina, Y. N.; Biswas, S.; Rajanbabu, T. V. J. Am. Chem. Soc. 2014, 136, 6215. (e) Larsen, C. R.; Erdogan, G.; Grotjahn, D. B. J. Am. Chem. Soc. 2014, 136, 1226. (4) (a) Beharry, A. A.; Woolley, G. A. Chem. Soc. Rev. 2011, 40, 4422. (b) Merino, E.; Ribagorda, M. Beilstein J. Org. Chem. 2012, 8, 1071. (c) Gautier, A.; Gauron, C.; Volovitch, M.; Bensimon, D.; Jullien, L.; Vriz, S. Nat. Chem. Biol. 2014, 10, 533. (d) Hu, Y.; Tabor, R. F.; Wilkinson, B. L. Org. Biomol. Chem. 2015, 13, 2216. (5) IUPAC definition of microscopic reversibility: In a reversible reaction, the mechanism in one direction is exactly the reverse of the mechanism in the other direction. This does not apply to reactions that begin with a photochemical excitation. (6) Examples of the cis−trans isomerizations of stilbenes: (a) Hammond, G. S.; Saltiel, J. J. Am. Chem. Soc. 1962, 84, 4983. (b) Hammond, G. S.; Saltiel, J. J. Am. Chem. Soc. 1963, 85, 2515. (c) Hammond, G. S.; Saltiel, J.; Lamola, A. A.; Turro, N. J.; Bradshaw, J. S.; Cowan, D. O.; Counsell, R. C.; Vogt, V.; Dalton, C. J. Am. Chem. Soc. 1964, 86, 3197. (7) For examples of cis−trans isomerizations of styrenes, see: (a) Arai, T.; Sakuragi, H.; Tokumaru, K. Chem. Lett. 1980, 9, 261. (b) Arai, T.; Sakuragi, H.; Tokumaru, K. Bull. Chem. Soc. Jpn. 1982, 55, 2204. (8) Metternich, J. B.; Gilmour, R. Synlett 2016, 27, 2541. (9) Singh, K.; Staig, S. J.; Weaver, J. D. J. Am. Chem. Soc. 2014, 136, 5275. (10) (a) Metternich, J. B.; Gilmour, R. J. Am. Chem. Soc. 2015, 137, 11254. (b) Metternich, J. B.; Artiukhin, D. G.; Holland, M. C.; von Bremen-Kühne, M.; Neugebauer, J.; Gilmour, R. J. Org. Chem. 2017, 82, 9955. (11) Metternich, J. B.; Gilmour, R. J. Am. Chem. Soc. 2016, 138, 1040. (12) Yao, R.; Zhao, Y.; Liu, T.; Huang, C.; Xu, S.; Sui, Z.; Luo, J.; Kong, L. Plant Mol. Biol. 2017, 95, 199. (13) Matern, U.; Lüerm, P.; Kreusch, D. Biosynthesis of Coumarins. In Comprehensive Natural Product Chemistry, Vol. 1: Polyketides and Other Secondary Metabolites; Sankawa, U., Ed.; Pergamon: Oxford, 1999. (14) Majumdar, N.; Paul, N. D.; Mandal, S.; de Bruin, B.; Wulff, W. D. ACS Catal. 2015, 5, 2329. (15) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (b) Meanwell, N. A. J. Med. Chem. 2011, 54, 2529. (16) SciFinder Scholar, 2017; SciFinder search was performed with substructure search type and exact specification of the chromene 4position substitution (accessed November 30, 2017). (17) Leroux, F. ChemBioChem 2004, 5, 644. (18) Substrates were prepared via a nonselective Horner−Wadsworth−Emmons reaction and separated (see SI). Only the Z-isomer was used for the study to facilitate analysis. (19) Lee, G. A.; Israel, S. H. J. Org. Chem. 1983, 48, 4557. (20) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841. (21) Zafrani, Y.; Yeffet, D.; Sod-Moriah, G.; Berliner, A.; Amir, D.; Marciano, D.; Gershonov, E.; Saphier, S. J. Med. Chem. 2017, 60, 797. (22) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Verdecchia, M. Synlett 2006, 2006, 909. (23) (a) Dexter, D. L. J. Chem. Phys. 1953, 21, 836. (b) Porter, G.; Wilkinson, F. Proc. R. Soc. London, Ser. A 1961, 264, 1. (24) (a) Cai, W.; Fan, H.; Ding, D.; Zhang, Y.; Wang, W. Chem. Commun. 2017, 53, 12918. (b) Zhan, K.; Li, Y. Catalysts 2017, 7, 337.
mimic the photochemical isomerization step in phenylpropanoid biosynthesis, attention was focused on the final intramolecular cyclization. Previous mechanistic delineation from this laboratory demonstrated that an ortho-substituent on the aryl ring of the chromophore is advantageous in ensuring high levels of stereoselectivity.10b This can be rationalized based on the augmentation of unfavorable nonbonding interactions in the product, which further hinders reconjugation of the π-system and subsequent excitation. Simple ortho-bromo substrates were prepared which were unlikely to compromise isomerization efficiency but would allow intramolecular cyclization under Pd catalysis (Scheme 3). Isomerization selectivities were good to excellent in almost all cases examined (E/Z >95:5, for p-H, Cl, and F, E/Z 85:15 for the naphthyl, and E/Z 72:28 for the p-CH3 derivative). Intramolecular cyclization employing Pd(OAc)2 and dppf, in combination with NaOtBu as a base in toluene (110 °C),22 delivered 4-CF3 2H-chromenes 3n−r in synthetically useful yields (up to 96%). Importantly, the starting Z-configured allylic alcohols do not undergo cyclization to afford 2Hchromenes even at elevated temperatures. Inspired by the spatiotemporal blueprint of phenylpropanoid biosynthesis, a direct route to medicinally relevant 2H-chromenes is disclosed. Efficient and selective isomerization of a pre-existing alkene (E/Z ratios up to >95:5) is catalyzed by inexpensive, commercially available anthracene (Sigma-Aldrich, reagent grade 97%, 100 g = $55.50) and likely proceeds via a triplet energy transfer manifold.6−8,23 This study contributes to the current interest in photocatalytic isomerization reactions.24 Installation of the CF3 unit effectively suppresses the photochemical degradation pathways of allylic alcohols. Combining the initial photocatalysis step with Pd-mediated cyclization constitutes a rapid approach to this privileged heterocyclic nucleus.
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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.7b03859. Experimental procedures and characterization data (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Ryan Gilmour: 0000-0002-3153-6065 Author Contributions †
S.I.F. and J.B.M. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We acknowledge financial support from the WWU Münster, Deutsche Forschungsgemeinschaft (Excellence Cluster EXC 1003) and Fonds der Chemischen Industrie (Fellowship to J.B.M.).
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REFERENCES
(1) Pearson, C. M.; Snaddon, T. ACS Cent. Sci. 2017, 3, 922. (2) Vasseur, A.; Bruffaerts, J.; Marek, I. Nat. Chem. 2016, 8, 209. (3) E→Z alkene isomerization via organometallic catalysis: (a) Pünner, F.; Schmidt, A.; Hilt, G. Angew. Chem., Int. Ed. 2012, 51, 1270. (b) Zhuo, 727
DOI: 10.1021/acs.orglett.7b03859 Org. Lett. 2018, 20, 724−727
