Letter pubs.acs.org/OrgLett
Development of a sp2−sp3 Stille Cross-Coupling for Rapid Synthesis of HIV NNRTI Doravirine Analogues Abdellatif ElMarrouni,* Mark Campbell, James J. Perkins, and Antonella Converso Department of Discovery Chemistry, MRL, Merck & Co., Inc., 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States S Supporting Information *
ABSTRACT: The development of a C(sp2)−C(sp3) cross-coupling reaction for rapid, parallel synthesis of analogues of two HIV NNRTI clinical candidates is described. This method allowed easy access to the C-ring space using a practical alkylation with commercially available tributyl(iodomethyl)stannane followed by a palladiumcatalyzed coupling with a variety of aryl halides (I, Br) in the presence of copper chloride. Optimization and scope of this method are reported.
T
As shown in Figure 1, candidates 1 and 2 have a similar molecular architecture based on an A−B−C ring system, a common structural feature in NNRTIs. The medicinal chemistry and development routes to access 2 relied on the same late-stage alkylation step as MK-49658 to introduce the corresponding triazolinone moiety 49 (Scheme 1). Whereas this bond
he World Health Organization (WHO) estimated in 2015 that approximately 37 million people worldwide were living with human immunodeficiency virus (HIV).1 Highly active antiretroviral therapy (HAART) is currently the most common treatment for individuals with HIV.2 HAART is a combination of medicines: nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and/or integrase strand inhibitors (InSTIs). In general, this therapy is very effective at helping the patient to decrease the total burden of HIV while maintaining the function of the immune system to prevent opportunistic fatal infections.3 HIV-infected patients are no longer under a potential life-threatening diagnosis; instead, they are confronted with a chronically managed disease.4 Whereas the first generation of antiviral agents (i.e., nevirapine, efavirenz, and delavirdine) has proven to be effective, the durability of HAART can be compromised due to the propensity of HIV to rapidly mutate. In this context, MK-4965 (1)5 and doravirine (2)6 are two clinical candidates designed to overcome the mutation profile of the first generation agents and improve the standard of care (Figure 1).7
Scheme 1. (A) Development Route to Doravirine and (B) Synthetic Strategy To Access Analogues of Doravirine
disconnection produced the final products in high yield, it is less attractive for developing structure−activity relationship (SAR) of the C-ring vector. The preparation of the corresponding C-ring 4 from commercial starting materials required a minimum of four independent steps. In contrast, numerous aryl and heteroaryl halides are readily available from commercial sources. We envisioned a crosscoupling reaction as the final step to rapidly synthesize a large array of analogues in a practical way. Palladium-catalyzed C(sp3) cross-coupling reactions have become important methods in the preparation of complex Figure 1. Structure of current NNRTI drugs and clinical candidates MK-4965 and doravirine. © 2017 American Chemical Society
Received: April 14, 2017 Published: June 7, 2017 3071
DOI: 10.1021/acs.orglett.7b01142 Org. Lett. 2017, 19, 3071−3074
Letter
Organic Letters organic molecules.10 Some of the earliest examples of sp2−sp3 Stille couplings required activation of the sp3 carbon by an allylic group.11 Early work by Migita’s group reported the crosscoupling reaction of methoxymethyl and hydroxymethylstannanes with aryl bromides.12 Falck and co-workers demonstrated the coupling using tributylstannanes with activated αacyloxy groups at C(sp3) centers.13,14 This Stille reaction has been extended to N-[(tributylstannyl)methyl]phthalimides.15 Similarly, azastannatranes, which have an internal coordination of a tertiary nitrogen, can be used to transfer C(sp3) groups to alkenyl or aryl halides.16 Alternatively, trifluoroborate salts can be utilized in sp2−sp3 coupling under Suzuki-type conditions,17 and more recently, Molander’s research group reported a photoredox method to form new C−C bonds.18 In this work, we describe the successful application of a palladium-catalyzed sp2−sp3 crosscoupling of a fully elaborated inactivated organostannane compound 5 with a range of aryl halides to prepare analogues of HIV NNRTI candidates and quickly build a SAR. Our initial strategy was focused on a Pd cross-coupling of advanced trifluoroborate intermediate 7 to introduce several aryls at a late stage to facilitate screening of the C-ring vector. However, attempts to install the trifluoroborate group proved unsuccessful; the alkylation reaction between pyridone 3 and the commercially available potassium bromomethyltrifluoroborate (6) proceeded poorly, and isolation of 7 proved difficult (Scheme 2). Based on these results, we also evaluated alkylation of the
Scheme 3. Catalyst and Solvent Screening of sp2−sp3 Stille Coupling of 5- and 3-Bromopyridinea
a
Ratio of products was determined by crude LC-MS spectra using an internal standard. See Supporting Information for details. bReaction conditions: 5 (25 mg, 1.0 equiv), KF (2.0 equiv), CuCl (2.0 equiv), 3bromopyridine (1.5 equiv), and Pd catalyst (0.1 equiv) in 1,4-dioxane (400 μL) at 90 °C for 16 h. cReaction conditions: 5 (25 mg, 1.0 equiv), KF (2.0 equiv), CuCl (2.0 equiv), 3-bromopyridine (1.5 equiv), and JackiePhos Pd G3 (0.1 equiv) in solvent (400 μL) at 90 °C for 16 h. See Supporting Information for details.
Scheme 2. Preparation of Organometallic Intermediate
Figure 2. Structures of palladium precatalysts: JackiePhos Pd G3, t-Bu BrettPhos Pd G3, and Xphos Pd G2.
byproduct 10. Next, we evaluated various solvents utilizing JackiePhos Pd G3 as common catalyst. Alcoholic solvents such as t-amyl alcohol (t-amylOH) and t-BuOH produced the desired product with high conversion and no significant byproduct detected. 1,2-Dimethoxyethane provided good results, whereas 2-methyltetrahydrofuran proved to be the less efficient solvent. No reaction was observed with cyclopentyl methyl ether and N,N-dimethylformamide. Toluene was a poor solvent that led to 9 as the major product with only 33% reaction conversion. This observation was in alignment with reported mechanistic studies that showed strong donor solvents can coordinate and stabilize the highly reactive unsaturated palladium(0) species generated during the catalytic cycle.23 Whereas the results of precatalysts XPhos Pd G2 and t-Bu BrettPhos Pd G3 are comparable to those of JackiePhos Pd G3, we decided to pursue our studies with XPhos Pd G2 due to its commercial availability and cost.24 Therefore, XPhos Pd G2 and t-BuOH were identified as the most efficient conditions to explore the scope of the reaction. These conditions were applied to all cross-coupling reactions without further optimization. Numerous aryl bromides and iodides were selected as crosscoupling partners to explore the scope of the transformation, as shown in Scheme 4. The corresponding products (11−26) were obtained in moderate to excellent isolated yields (44−94%). The reaction conditions proved compatible with a variety of
pyridone 3 with commercially available tributyl(iodomethyl)stannane (8), resulting in the isolation of desired organostannane 5 in excellent yield. Optimization of reaction conditions for coupling 5 and aryl bromides was studied using 3-bromopyridine. Initial screening based on modification of the work of Biscoe’s group16b showed that reactions were most efficient in the presence of JackiePhos palladium precatalyst19 and stoichiometric amounts of copper chloride and potassium fluoride in 1,4-dioxane as solvent.20 As previously reported, the function of the copper salt is to accelerate the transmetalation step while potassium fluoride scavenges the tin byproduct.21 Further optimization by screening catalysts and solvents was studied with the objective of increasing the ratio of desired product 9 to reduced byproduct 10 (Scheme 3). Traditional palladium catalysts such as Pd(PPh3)4 and Pd(dppf)Cl2 provided no desired product. The catalysts with the highest 9/10 ratio were biarylphosphine precatalysts such as JackiePhos Pd G3, t-Bu BrettPhos Pd G3, and XPhos Pd G2 developed by the Buchwald group (Scheme 3 and Figure 2).22 These commercially available precatalysts are effective as the palladacycles offer high turnover while the bulky electron-deficient ligands promote rapid reductive elimination and decrease the amount of reduced 3072
DOI: 10.1021/acs.orglett.7b01142 Org. Lett. 2017, 19, 3071−3074
Letter
Organic Letters
with reduced byproduct 30 in 90:10 ratio and 50% isolated yield (Scheme 4). To explore the scope of the reaction with organostannane 28, we examined a small set of aryl bromides and iodides (Scheme 6).
Scheme 4. Scope of Cross-Coupling of Organostannane 5 with Aryl Halides (Br, I)a
Scheme 6. Cross-Coupling of Organostannane 28 with Aryl Halides (Br, I)
The desired products 31−36 were isolated in moderate to excellent yields (50−97%). In addition to the substituents present on organostannane intermediate 28 (two aryl chlorides and a cyano group), the reaction conditions tolerated electrondonating and electron-withdrawing groups, including methoxy, cyano, nitro, and fluoro substituents on the aryl group. Thus, these results demonstrated again the versatility and robustness of this cross-coupling reaction. This palladium-catalyzed sp 2−sp3 coupling provides a complementary method to build carbon−carbon bonds that couple an N- or O-methyl nucleophile with aryl halide electrophiles that provides an alternate route to new analogues from the traditional N− or O−carbon bond formation between the nucleophilic heteroatom and benzyl halide electrophiles. A significant advantage is that there are many more commercially available aryl halides than benzyl halides, thereby supporting easier access to large libraries of compounds. A second benefit is that both intermediates 5 and 28 were easily prepared on gram scale and proved stable.25 The cross-coupling reaction conditions of these organostannanes are compatible with a variety of functional groups and may be introduced early or late in synthetic strategies. We have succeeded in devising an effective system to prepare analogues of doravirine and MK-4965 to quickly evaluate alternative C-rings and build a SAR. Particularly noteworthy is that we have also demonstrated the use of a sp2− sp3 Stille cross-coupling in advanced therapeutic compounds. These findings may prove to be relevant for complementing the Pd-based cross-coupling of unactivated alkylstannanes and open up the possibility of expanding the scope of organic and medicinal chemists’ toolbox.
a
Ratio of products was determined by crude LC-MS spectra using an internal standard. See Supporting Information for details.
functional groups of different electronic nature, including methoxy (12−14), cyano (15−17), nitro (19−22), and fluoro (25−26) substituents. In addition, the groups present in the substrate (chloro, cyano, and CF3) were tolerated under the coupling conditions. Aryl bromides provided similar results to aryl iodides, rendering these coupling conditions general for both halide groups. Moreover, no significant impact of the steric effects was observed when comparing ortho-, meta-, and parasubstituents on the aryl group. Next, we turned our attention to applying this approach to the MK-4965 core (Scheme 5). The organostannane intermediate 28 was prepared by alkylation of readily available phenol 278 with iodomethylstannane 8 (K2CO3, DMF, 25 °C, 81%). The crosscoupling reaction of 28 was evaluated with 3-bromopyridine using the previously optimized conditions (XPhos Pd G2, CuCl, KF, and t-BuOH), which provided the desired product 29 along Scheme 5. Preparation of Organostannane 28 and Evaluation of Cross-Coupling with 3-Bromopyridine
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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.7b01142. Detailed experimental procedures, analytical and spectral data for all new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
a
Ratio of products was determined by crude LC-MS spectra using an internal standard. See Supporting Information for details.
Abdellatif ElMarrouni: 0000-0001-5408-0374 3073
DOI: 10.1021/acs.orglett.7b01142 Org. Lett. 2017, 19, 3071−3074
Letter
Organic Letters Notes
(14) During the preparation of this paper, Walczak and co-workers reported the synthesis of C-aryl glycosides using a stereospecific palladium-catalyzed coupling of anomeric stannanes: Zhu, F.; Rourke, M. J.; Yang, T.; Rodriguez, J.; Walczak, M. A. J. Am. Chem. Soc. 2016, 138, 12049−12052. (15) Malova Krizkova, P.; Hammerschmidt, F. Eur. J. Org. Chem. 2013, 2013, 5143−5148. (16) (a) Jensen, M. S.; Yang, C.; Hsiao, Y.; Rivera, N.; Wells, K. M.; Chung, J. Y. L.; Yasuda, N.; Hughes, D. L.; Reider, P. J. Org. Lett. 2000, 2, 1081−1084. (b) Li, L.; Wang, C.; Huang, R.; Biscoe, M. Nat. Chem. 2013, 5, 607−612. (17) (a) Sandrock, D. L.; Jean-Gerard, L.; Chen, C.-Y.; Dreher, S. P.; Molander, G. A. J. Am. Chem. Soc. 2010, 132, 17108−17110. (b) For review, see: Molander, G. A.; Sandrock, D. L. Curr. Opin. Drug Discov. Devel. 2009, 12, 811−823. (18) Tellis, J. C.; Primer, D. N.; Molander, G. A. Science 2014, 345, 433−436. (19) Hicks, J. D.; Hyde, A. M.; Cuezva, A. M.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 16720−16734. (20) See Supporting Information for initial screening results. (21) Mee, S.; Lee, V.; Baldwin, J. Angew. Chem., Int. Ed. 2004, 43, 1132−1136. (22) (a) For a review, see: Bruno, N. C.; Buchwald, S. L. Strem Chemiker 2014, 1, 1−15. (b) Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Chem. Sci. 2013, 4, 916−920. (23) (a) Dyson, P. J.; Jessop, P. G. Catal. Sci. Technol. 2016, 6, 3302− 3316. (b) Vikse, K.; Naka, T.; McIndoe, J. S.; Besora, M.; Maseras, F. ChemCatChem 2013, 5, 3604−3609. (c) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461−1473. (24) Price for catalysts from Sigma-Aldrich: JackiePhos Pd G3 $415/g; t-Bu BrettPhos Pd G3 $285.5/g; XPhos Pd G2 $118/g. (25) No decomposition was observed after 10 months stored at 4 °C.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We gratefully acknowledge Christopher Cox and Christopher S. Burgey (Merck & Co., Inc., Kenilworth, NJ, USA) for general assistance, Scott Ceglia, Wilfredo Pinto, and Rosina O. Ayore (Merck & Co., Inc., Kenilworth, NJ, USA) for analytical assistance, Janine Brouille (Merck & Co., Inc., Kenilworth, NJ, USA) for NMR assistance, and Louis-Charles Campeau and Jaume Balsells (Merck & Co., Inc., Kenilworth, NJ, USA) for discussion.
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