Introduction of Trifluoroethylamine as Amide Isostere by C–H

Letter pubs.acs.org/OrgLett

Introduction of Trifluoroethylamine as Amide Isostere by C−H Functionalization of Heteroarenes Marie-Gabrielle Braun,*,† Georgette Castanedo,† Ling Qin,‡,§ Patrick Salvo,†,§ and Samir Z. Zard*,‡ †

Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States Laboratoire de Synthèse Organique, UMR 7652 CNRS-École Polytechnique, Route de Saclay, 91128 Palaiseau Cedex, France

‡

S Supporting Information *

ABSTRACT: A direct and efficient introduction of a trifluoroethylamine motif into various heteroaromatic structures, using a readily available xanthate S-[1-(N-acetylamino)2,2,2-trifluoroethyl]-O-ethyl dithiocarbonate (5), is reported. Medicinally relevant trifluoroethylaminated heteroarenes containing a wide range of functional groups were successfully synthesized under mild conditions. This amide isostere could be introduced into both electron-rich and -poor heteroarenes to give the desired products in one step. The beneficial effect of camphorsulfonic acid (CSA) was also demonstrated with electrondeficient heteroarenes.

T

access to trifluoroethylamine substituted heteroaromatics using an intermolecular oxidative radical addition of xanthates.5

rifluoroethylamines have been proposed to be amide isosteres capable of modulating ADME properties.1 For example, amide-to-trifluoroethylamine isosterism in clinical cathepsin K inhibitor (Odanacatib,2 Figure 1) improved

Scheme 1. Access to Trifluoroethylated Amines by Prefunctionalization of the Core or by Direct C−H Functionalization

In an effort to identify a synthesis of trifluoroethylamines that would obviate the need for substrate prefunctionalization, we considered whether the trifluoroethylamination could proceed instead by C−H functionalization of simple heteroaromatic substrates using the readily available xanthate S-[1-(Nacetylamino)-2,2,2-trifluoroethyl]-O-ethyl dithiocarbonate (5).6 We recognized that the xanthate mediated intermolecular oxidative radical alkylation provides such a platform while retaining high functional group tolerance. After initiation by dilauroyl peroxide (DLP; sometimes sold under lauroyl peroxide or laurox), the N-acetyl-α-trifluoroethylamine radical 6, derived from xanthate 5,7 can add to 3-substituted indoles 7 at the C2 position to give a benzyl radical 8 (Scheme 2). This radical can follow two competing pathways: one is the regeneration of radical 6 and starting indole 7 by reversible radical fragmentation; the other is the oxidation of radical 8 into the corresponding cation 9 by a single electron transfer to the peroxide. Rearomatization of cation 9 furnishes the 2,3disubstituted indole products 10. This system has proven remarkably efficient for the introduction of acetate, propionate,

Figure 1. Relevance of trifluoroethylated amine surrogates in medicinal chemistry.

metabolic stability while maintaining a good level of potency. Several trifluoroethylated amines such as compounds 1−4 exhibit interesting biological activity (Figure 1).3 Despite the fact that amides are widely found in drugs, further applications of amidebond substitution by trifluoroethylamine surrogates are scarce, most likely due to the lack of convenient synthetic methods. Current approaches toward trifluoroethylamine surrogates require multistep synthesis and highly prefunctionalized substrates. Their preparation mostly hinges on the reductive or alkylative amination of the corresponding trifluoromethylketones, the reduction of trifluoromethylated enamines, the addition of nucleophiles to trifluoromethyl iminium species, and the addition of the trifluoromethyl anion to functionalized imines (Scheme 1).4 Herein, we report a direct and metal-free © 2017 American Chemical Society

Received: June 20, 2017 Published: July 20, 2017 4090

DOI: 10.1021/acs.orglett.7b01880 Org. Lett. 2017, 19, 4090−4093

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Organic Letters

carbocation, tert-butyl hydroperoxide was added as a co-oxidant to promote the oxidation step (Table 1, entry 4). However, the desired product 10a was produced in only 22% yield. Recognizing that the fast decomposition of DLP10 at relatively high reaction temperature might increase the probability of dimerization of radicals or other side reactions and cause an inefficient oxidation step for lack of oxidant,11 we conjectured that a lower reaction temperature should favor the conversion to the desired product. At 65 °C, the anticipated 2-alkylated indole 10a was obtained in a slightly higher yield (51%) (Table 1, entry 5). Encouraged by these results, we explored the reaction of indole-3-carbaldehyde 7a and xanthate 5 by further lowering the reaction temperature to 50 °C, at which point the half-life of DLP is prolonged to approximately 24 h.10 As shown in Table 1, the lower reaction temperature seemed to give a suitable generation rate of initiating radicals, which maintained an appropriate concentration of adduct radicals in the presence of a large amount of DLP. At lower temperature, the lower concentration of reactive radicals reduced side reactions and the excess of DLP as oxidant promoted the oxidation state. At 50 °C, the desired reaction could occur efficiently and gave a useful yield of the expected 2,3-disubstituted indole 10a. Having established conditions suitable for the trifluoroethylamination of indole-3-carbaldehyde 7a, we proceeded to examine the substrate scope of the method (Table 2). Electron-rich heteroarenes bearing a broad range of electron-deficient functional groups were found to be competent substrates, delivering products with aldehydes (10a, 10h, and 10j), ketones (10b and 10i), esters (10c and 10d), and nitriles 10e. Between 2.5 and 5.0 equiv were necessary to observe complete conversion, which translates into a 45 to 135 h reaction time. No effort was made to shorten the reaction times, but ongoing work on related transformations indicates that this is indeed possible. There is a single report by Minisci and co-workers on the modification of the Barton−McCombie reaction to add cyclohexyl radicals to lepidine, 4-cyanopyridine, quinoline, and isoquinoline. However, there are no examples involving cleavage of the sulfide bond in xanthate to accomplish such additions as in the present work.12 From these results, the radical additions with substrates bearing electron-withdrawing groups were more efficient than those with electron-donating groups (entry 6). Although both electron-donating and -withdrawing groups can stabilize the radical intermediate (8, Scheme 2), the latter offers better stabilization through an additional resonance effect. Conversely in the case of 10f, the reverse fragmentation to regenerate the initial radical 6 and starting indoles 7 is easier, leading to an inefficient oxidation step and promoting the side reactions. Benzothiophene, pyrroles, and caffeine can also be functionalized albeit with a lower yield in the case of the benzothiophene (entries 8−11). We decided to expand the scope of this reaction to include pyridines13 and pyrimidines since they are found in >100 currently marketed drugs14 and are widely distributed in natural products, pharmaceuticals, ligands, and functional materials.15 From previous studies, we knew that free pyridines possess sufficient nucleophilicity to react with the xanthate group by ionic pathways.16 Addition of an acid serving both to neutralize the basic pyridine nitrogen and to activate the pyridine nucleus toward radical addition is therefore mandatory. In this respect, camphorsulfonic acid (CSA), used previously by Barton and coworkers, was selected.17 It is an inexpensive strong acid that is available in free-flowing anhydrous form. Moreover, the corresponding salts are readily soluble in many organic solvents.

Scheme 2. Proposed Mechanism for the Intermolecular Radical Addition

and ketonyl groups into electron-rich heteroaromatic structures such as indoles, pyrroles, thiophenes, and furans.8 However, it was apparent at the outset of our studies that addition of the trifluoroethylamine radical would present several challenges. On one hand, in contrast to previous reports in which the radical is electrophilic typically of the α-carbonyl type, the N-acetyl αtrifluoroethylamine radical 6 is regarded as a modestly nucleophilic radical. As a result, the addition of radical 6 is expected to be more challenging in the case of electron-rich heteroarenes. On the other hand, the oxidation step by the DLP should be easier with electron-rich heteroarene 7. Furthermore, it has also been shown that exposure of reagent 5 alone to a stoichiometric amount of lauroyl peroxide furnished a surprisingly good yield of the dimer.9 With these considerations in mind, our investigations began with an examination of the oxidative alkylation of indole-3carbaldehyde 7a with acetyl-protected xanthate 5 using DLP as both radical initiator and oxidant in ethyl acetate at reflux (Table 1, entry 1). The desired product 10 was obtained in an Table 1. Evaluation of the Reaction Conditions for the Trifluoroethylamination Reaction

entryb

solvent

temp (°C)

additive

yield (%)c

1 2 3 4 5 6

EtOAc DCE DCE DCE DCE DCE

reflux reflux reflux reflux 65 90

− − K2PO4 tert-BuH2O2 − −

17 44 16 22 51 60

a

In a stoichiometric amount, added portionwise until complete conversion. bReactions carried out on a 0.5 mmol scale. cIsolated yield.

encouraging 17% yield. In an effort to improve the yield of this promising result, we turned our attention to another solvent typically used for xanthate based radical reactions: 1,2-dicholoroethane (DCE). At reflux, the desired 2-alkylated indole-3carbaldehyde 10a was formed in 44% yield (Table 1, entry 2). Since the indole might be protonated by the lauric acid formed, thus affecting the intermolecular radical addition step, neutralization by addition of a weak inorganic base, such as K2HPO4, was investigated. This resulted in the formation of adduct 10a in a poor 16% yield (Table 1, entry 3). Considering that DLP might not be strong enough to oxidize the adduct radical to the 4091

DOI: 10.1021/acs.orglett.7b01880 Org. Lett. 2017, 19, 4090−4093

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Organic Letters Table 2. Scope of the Trifluoroethylamination Reaction for Electron-Rich Heteroarenesa

Table 3. Scope of the Trifluoroethylamination Reaction for Electron-Deficient Heteroarenesa

a

Reaction conditions: heteroarene 7 (1.0 equiv), xanthate 5 (2.0 equiv); CSA (1.0 equiv), DCE (0.5 M), lauroyl peroxide was added in 50 mol %/18 h portions (with respect to the heteroarene). bIsolated yields.

hydrolysis of the acetamide protecting group. This is illustrated by the conversion of 10c into 11. In cases where the substrate might be incompatible with harsh conditions, it is possible to use the Boc-protected analog 13 which can be cleaved under much milder conditions (Scheme 3). C−H activation approaches can be particularly useful as applied to the direct functionalization of bioactive natural products or drug candidates. To demonstrate this potential, we subjected the core of a BTK inhibitor to xanthate 5 under the usual a

Reaction conditions: heteroarene 7 (1.0 equiv), xanthate 5 (2.0 equiv); DCE (0.5 M), lauroyl peroxide was added in 50 mol %/18 h portions (with respect to the heteroarene until complete conversion). b Isolated yield.

Scheme 3. Access to Trifluoroethylamine Products by Acetate Deprotection and Intermolecular Radical Addition Using NBoc Xanthate 12

We were pleased to find that the addition proceeded as expected and furnished the acetamido trifluoroethyl adducts 10 in variable but nevertheless useful yields (Table 3). For compound 10p, further work is needed to identify the side products and to explain the absence of other isomers. Various substituents are tolerated, with particular attention drawn to the bromine in example 10o, which could be further elaborated through various transition metal coupling reactions (Heck, Suzuki, etc.). The addition could also be applied to the pyrimidine series 10r. Most of these compounds would be tedious to access by alternative routes. Furthermore, the free amines can be obtained by standard acid 4092

DOI: 10.1021/acs.orglett.7b01880 Org. Lett. 2017, 19, 4090−4093

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Organic Letters trifluoroethylamination reaction conditions (Scheme 4).18 In the event, trifluoroethylaminated heteroarene 10s was isolated in

LeRiche, T.; Li, C. S.; Masse, F.; McKay, D. J.; Nicoll-Griffith, D. A.; Oballa, R. M.; Palmer, J. T.; Percival, M. D.; Riendeau, D.; Robichaud, J.; Rodan, G. A.; Rodan, S. B.; Seto, C.; Therien, M.; Truong, V.-L.; Venuti, M. C.; Wesolowski, G.; Young, R. N.; Zamboni, R.; Black, W. C. Bioorg. Med. Chem. Lett. 2008, 18, 923. (3) (a) Trotter, B. W.; Nanda, K. K.; Burgey, C. S.; Potteiger, C. M.; Deng, J. Z.; Green, A. I.; Hartnett, J. C.; Kett, N. R.; Wub, Z.; Henze, D. A.; Della Penna, K.; Desai, R.; Leitl, M. D.; Lemaire, W.; White, R. B.; Yeh, S.; Urban, M. O.; Kane, S. A.; Hartman, G. D.; Bilodeau, M. T. Bioorg. Med. Chem. Lett. 2011, 21, 2354. (b) Holsinger, L. J.; Elrod, K.; Link, J. O.; Graupe, M.; Kim, I. J. WO-2009/055467 A2, 2009. (c) Bringmann, G.; Feineis, D.; Brueckner, R.; Blank, M.; Peters, K.; Peters, E. M.; Reichmann, H.; Janetzky, B.; Grote, C.; Clement, H. W.; Wesemann, W. Bioorg. Med. Chem. 2000, 8, 1467. (4) (a) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Synlett 2001, 2001, 77. (b) Mizuta, S.; Shibata, N.; Sato, T.; Fujimoto, H.; Nakamura, S.; Toru, T. Synlett 2006, 267. (c) Prakash, G. K. S.; Wang, Y.; Mogi, R.; Hu, J.; Mathew, T.; Olah, G. A. Org. Lett. 2010, 12, 2932. (5) For reviews on xanthates: (a) Quiclet-Sire, B.; Zard, S. Z. Pure Appl. Chem. 2010, 83, 519. (b) Quiclet-Sire, B.; Zard, S. Top. Curr. Chem. 2006, 264, 201. For an account of the discovery of the process, see: (c) Zard, S. Z. Aust. J. Chem. 2006, 59, 663. For applications to total synthesis, see: (d) Quiclet-Sire, B.; Zard, S. Z. Isr. J. Chem. 2017, 57, 202. (6) For a review on the synthesis of heteroarenes: El Qacemi, M.; Petit, L.; Quiclet-Sire, B.; Zard, S. Z. Org. Biomol. Chem. 2012, 10, 5707. (7) Gagosz, F.; Zard, S. Z. Org. Synth. 2007, 84, 32. (8) (a) Osornio, Y. M.; Cruz-Almanza, R.; Jiménez-Montaño, V.; Miranda, L. D. Chem. Commun. 2003, 18, 2316. (b) Reyes-Gutiérrez, P. E.; Torres-Ochoa, R. O.; Martínez, R.; Miranda, L. D. Org. Biomol. Chem. 2009, 7, 1388. (c) Flórez-López, E.; Gomez-Pérez, L. B.; Miranda, L. D. Tetrahedron Lett. 2010, 51, 6000. (d) Guerrero, M. A.; Miranda, L. D. Tetrahedron Lett. 2006, 47, 2517. (e) Chay, C. I.; Cansino, R. G.; Pinzón, C. I.; Torres-Ochoa, R. O.; Martínez, R. Mar. Drugs 2014, 12, 1757. (f) Pérez, V. M.; Fregoso-López, D.; Miranda, L. D. Tetrahedron Lett. 2017, 58, 1326. (g) Quiclet-Sire, B.; Revol, G.; Zard, S. Z. Org. Lett. 2009, 11, 3554. (h) Quiclet-Sire, B.; Zard, S. Z. Heterocycles 2010, 82, 263. (i) Han, S.; Zard, S. Z. Org. Lett. 2014, 16, 5386. (9) Gagosz, F.; Zard, S. Z. Org. Lett. 2003, 5, 2655. (10) In refluxing 1,2-dicholoroethane (temp = ∼85 °C), the half-life of DLP is about 60 min. Zang, N.; Qian, X.-M.; Liao, J. Y.; Shu, C.-M. J. J. Taiwan Inst. Chem. Eng. 2014, 45, 461. (11) The presence of low polarity side products observed by TLC appears to be responsible for the low yield obtained. (12) For a review on functionalization of azides: Murakami, K.; Yamada, S.; Kaneda, T.; Itami, K. Chem. Rev. 2017, ASAP. DOI: 10.1021/ acs.chemrev.7b00021. (13) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In Alkaloids: Chemical and Biological Perspectives; Pelletier, W. W., Ed.; Elsevier: New York, 1999; Vol. 13, p 92. (14) (a) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627. (b) Arena, C. G.; Arico, G. Curr. Org. Chem. 2010, 14, 546. (c) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B. Chem. Rev. 2012, 112, 2642. (15) Coppa, F.; Fontana, F.; Minisci, F.; Pianese, G.; Tortoreto, P.; Zhao, L. Tetrahedron Lett. 1992, 33, 687. (16) Castro, E. A. Chem. Rev. 1999, 99, 3505. (17) Barton, D. H. R.; Garcia, B.; Togo, H.; Zard, S. Z. Tetrahedron Lett. 1986, 27, 1327. (18) Crawford, J. J.; Ortwine, D. F.; Wei, B.; Young, W. B. Patent: EP2773638 B1, 2015.

Scheme 4. Late-Stage Functionalization of the Core of a BTK Inhibitor via Direct Allylic C−H Trifluoroethylamination

41% yield with complete selectivity for the pyrrole presumably due to the significant lower aromatic character of the pyrrole nucleus in comparison to the pyridine ring. This lowers the energetic barrier for the reversible radical addition resulting in the observed regioselectivity. In conclusion, this strategy has provided the first examples of intermolecular addition on electron-deficient heteroarenes using the xanthate technology. The present C−H functionalization approach has functional group tolerance and is experimentally simple to perform and inexpensive. These aspects combine to provide a particularly useful tool for the direct introduction of trifluoroethylamino groups into bioactive natural products or drug candidates.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01880. Typical experimental procedure and characterization for all products (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Marie-Gabrielle Braun: 0000-0002-0837-9719 Georgette Castanedo: 0000-0003-4584-6715 Samir Z. Zard: 0000-0002-5456-910X Present Address §

P.S. is now at Gilead, Foster City, CA, and L.Q. is now at the University of Texas Southwestern Medical Center, Dallas, TX. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to thank Baiwei Lin (Genentech) and Kewei Xu (Genentech) for HRMS data and Qi Huang (Ecole Polytechnique) for experimental assistance. An Ecole Polytechnique Scholarship to L.Q. is also gratefully acknowledged.

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REFERENCES

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DOI: 10.1021/acs.orglett.7b01880 Org. Lett. 2017, 19, 4090−4093