Article Cite This: Organometallics XXXX, XXX, XXX−XXX
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Xantphos as a Branch-Selective Ligand for the Acyclic sec-Alkyl Negishi Cross-Coupling of Heteroaryl Halides Alan H. Cherney,* Simon J. Hedley, Steven M. Mennen, and Jason S. Tedrow Drug Substance Technologies, Amgen, Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States
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S Supporting Information *
ABSTRACT: We present the application of the common bidentate phosphine ligand Xantphos toward the highly selective Negishi cross-coupling of heteroaryl halides and acyclic sec-alkyl organozinc reagents to prepare pharmaceutically relevant motifs. Branched-to-linear ratios of >100:1 can be achieved for several substrates relevant to the pharmaceutical industry, and tolerance of certain acidic protons is exhibited. A high-throughput experimentation approach was taken to rapidly compare Xantphos Pd G3 to other selective Negishi coupling catalysts, leading to separate reactivity profiles for each methodology. The utility of Xantphos Pd G3 was demonstrated through the scale-up and isolation of a complex pyridine building block.
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INTRODUCTION
lower energy primary alkyl-Pd species, can lead to a mixture of branched and linear coupling products. Bulky bidentate phosphine ligands have long been known to minimize alkyl isomerization. Indeed, Hayashi reported in 1984 that bidentate ligands with large bite angles (i.e., dppf) inhibited β-hydride elimination in the Pd-catalyzed coupling of bromobenzene with organomagnesium and organozinc reagents (Figure 2a).5,6 Large bite angles were proposed to enforce a favorable geometry around the Pd center that placed the reacting alkyl fragments in close contact. van Leeuwen subsequently examined the role of bite angle in these reactions and discovered that further increases, as in the case of Xantphos, resulted in higher isomerization, possibly through distortion of the desired square planar geometry around Pd.7 Buchwald8 and Organ9 have recently shown that bulky monodentate phosphine and N-heterocyclic carbene (NHC) ligands can couple electronically perturbed (hetero)aryl halides with sec-alkylzinc reagents (Figure 2b).10 The rationale for the ligand design was that reductive elimination would be successfully accelerated by tuning the electron-donating ability of the ligands and the steric environment around Pd. We became interested in the above studies because of our desire to couple pyridyl halides with acyclic sec-alkylmetals. Pyridines are the second most common ring found in FDAapproved small-molecule drugs.11 As a result, discovery and process development teams desire protocols that can efficiently couple these heterocycles to other common building blocks.12 To support the progression of a drug candidate through clinical development, ligands that are readily available in bulk,
The widespread adoption of Pd-catalyzed transformations by the pharmaceutical industry has dramatically altered the landscape of accessible chemical space. Nonetheless, a reliance on sp2−sp2 couplings has limited the structural diversity of many compound libraries.1 Couplings at sp3-hybridized centers would improve access to diverse molecular architectures; however, competitive β-hydride elimination still remains a challenge for both alkyl electrophiles and alkylmetals (Figure 1).2−4 In a pathway unique to secondary alkyl fragments, a deleterious sequence of β-hydride elimination/migratory reinsertion/reductive elimination, driven by the formation of
Special Issue: The Roles of Organometallic Chemistry in Pharmaceutical Research and Development
Figure 1. Origin of branched and linear isomers in the cross-coupling of secondary organometallic reagents. O.A. = oxidative addition, T.M. = transmetalation, R.E. = reductive elimination, isom. = isomerization. © XXXX American Chemical Society
Received: August 16, 2018
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DOI: 10.1021/acs.organomet.8b00590 Organometallics XXXX, XXX, XXX−XXX
Article
Organometallics
Table 1. Catalyst Screen for the Negishi Cross-Coupling of 2-Bromopyridine
entry
catalyst
pdt/stda
b:lb
1 2 3 4 5 6 7 8 9 10 11 12
DavePhos Pd G3 RuPhos Pd G2 SPhos Pd G3 XPhos Pd G3 CPhos Pd G3 t BuXPhos Pd G3 BrettPhos Pd G3 Josiphos SL-J009-1 Pd G3 PtBu3 Pd G2 MorDalPhos Pd G3 BINAP Pd G3 Xantphos Pd G3 (C1)
0.88 0.89 0.89 0.83 0.89 0.33 0.68 0.36 0.74 0.42 0.63 0.88
8.7 7.2 7.2 0.5 2.2 0.7 2.2 0.8 0.5 0.5 5 97
a
pdt/std was calculated by HPLC by taking the LCAP ratio of 3 + 4 and 0.4 equiv external standard (biphenyl). bb:l was calculated on HPLC by taking the LCAP ratio of 3 and 4.
comparing Xantphos Pd G3 (C1) against both EtCPhos Pd G3 (C2) and PEPPSI IHept-Cl (C3) across 16 diverse substrates (Table 2). Our panel included aryl and heteroaryl halides, sterically encumbered substrates, compounds with sensitive functional groups, and acidic protons.14 Whereas published conditions for both C2 and C3 employ THF/ toluene mixtures, we elected to conduct our screening in THF to enable the solubility of a greater range of functionalized pyridyl halides, avoid confounding effects arising from heterogeneity, and facilitate our liquid-handling workflows. Reactions were run with both iPrZnBr and nPrZnBr to compare relative reactivity. In reactions with nPrZnBr, little isomerization to the branched product was detected. With respect to organozinc 2, whereas no single catalyst was optimal across the entire panel of substrates, certain catalysts were ideal for different subclasses. C1 provided >89:1 b:l ratio and high conversion by liquid chromatography area percentage (LCAP) for the parent 2-halopyridines (entries 1−3), outperforming C2 and C3. Unactivated 4-bromotoluene proved to be a challenging substrate and favored isomerized product for all three catalysts, although C3 provided the cleanest reactivity profile (entry 4). In contrast, C3 delivered 72:1 b:l ratio for an aryl halide bearing an electron-withdrawing group, surpassing the other two catalysts (entry 5). These results exemplify the relationship between substrate electronics, reductive elimination rates, and isomerization, which currently do not allow for a single catalyst solution for all coupling subclasses. Regarding hindered 3-substituted pyridines, C3 maintained the greatest selectivity for branched products. The b:l ratio for C1 decreased from 8:1 to 2:1 when switching from a 3-Me to a larger 3-CF3 group (entries 6 and 7). Overcoupling was more prevalent with C3 than with C1 in the reaction of 2-bromo-3chloropyridine, suggesting that selective functionalization might be possible using C1 (entry 8).15 A series of aminosubstituted pyridines, common motifs in drug frameworks, behaved best in the presence of C1, providing up to 100:1 b:l ratio and illustrating the tolerance of the Negishi coupling to
Figure 2. Catalyst development for the cross-coupling of secondary organozinc reagents.
ideally from multiple vendors and with limited patent protection, are favored. These considerations prompted us to re-evaluate the coupling of pyridyl halides with isopropyl-zinc halides. In this Article, we report our “hit-to-process” optimization to prepare a number of challenging isopropylpyridines using Xantphos,13 a common ligand that can supply high branched/linear (b:l) product ratios (Figure 2c).
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RESULTS AND DISCUSSION We began our investigation by screening a panel of common Pd precatalysts for the coupling of 2-bromopyridine (1) and i PrZnBr (2) (Table 1). All precatalysts could be procured on scale if necessary. Consistent with prior studies, Buchwald ligands SPhos and RuPhos gave moderate selectivity for desired product 3, whereas XPhos favored the isomerized linear product 4 (entries 2−4).8 Similarly, CPhos, a ligand optimized toward the Negishi coupling of certain aryl halides, displayed only mild selectivity for heteroaryl substrate 1 (entry 5).8a We were intrigued to find that the two bidentate ligands in our screen behaved well: BINAP and Xantphos provided 5:1 and 97:1 b:l, respectively (entries 11 and 12). On the basis of literature precedent (vide supra), we were surprised by the effectiveness of the C1-catalyzed transformation and questioned whether it was an anomaly. Therefore, we elected to deploy a high-throughput experimentation approach to rapidly evaluate the chemical space of the cross-coupling reaction. Using a Freeslate Jr. automated liquid handling system, we designed a head-to-head study B
DOI: 10.1021/acs.organomet.8b00590 Organometallics XXXX, XXX, XXX−XXX
Article
Organometallics Table 2. Negishi Cross-Coupling of (Het)aryl Halides and Isopropylzinc Bromidea
a
First entry is LCAP of Negishi coupling products, and second entry is LCAP ratio of b:l isomers. Reactions were run on a 0.3 mmol scale.
partner would also lead to a reduction in selectivity. Indeed, when coupling bromopyridine 1 with 2-butylzinc bromide in the presence of 4 mol % Xantphos Pd G3, an 11:1 b:l was achieved.16 To demonstrate the utility of C1, pyridine 5 was selected as a challenging substrate for further process development (Table 3). The active catalyst proved to be very robust, allowing Pd loadings to be reduced to 0.5 mol %.17 At these low loadings, we became concerned about the inhibitory ability of
certain acidic protons (entries 9−12). Several other challenging compounds were screened to gauge the compatibility of different functional groups (entries 13−16). In all cases, no product was observed when aldehyde functionality was present, whereas moderate yield and selectivity were seen with a nitropyridine. Both C1 and C3 delivered high selectivity with acetylpyridine derivatives (entry 14). As a result of the steric sensitivity observed using C1, we tested whether increasing the size of our organometallic C
DOI: 10.1021/acs.organomet.8b00590 Organometallics XXXX, XXX, XXX−XXX
Article
Organometallics Table 3. Salt Effects
Scheme 1. Process Development of a Pd/XantphosCatalyzed Negishi Coupling
entry
additive
conversion (%)a
1 2 3 4 5 6
ZnCl2b ZnBr2b MgCl2 MgBr2 LiCl
100 13 13 97 98 99
a Conversion was calculated by HPLC. bAfter 6 h, conversion was >95%.
stoichiometric ZnX2 byproducts on the catalytic cycle.18 Accordingly, we studied several reactions in the presence of excess salts. Whereas rapid conversion to product was observed in the absence of added salt, the inclusion of one equivalent of ZnCl2 or ZnBr2 to the reaction mixture led to sluggish reactivity. Alternatively, Mg and Li salts had little impact on conversion. On the basis of these results, we elected to minimize Zn salt formation by preparing our Zn reagent in situ from a 2:1 mixture of iPrMgCl and ZnCl2, both of which are readily available in bulk quantities. Critically, precipitated salts from the organozinc formation were essential, as filtering them off led to reduced reactivity. These changes had no impact on alkyl isomerization. We next turned our attention to developing a scalable isolation procedure. Basic aqueous work-ups resulted in the precipitation of Zn(OH)2 as a thick slurry.19 During acidic aqueous work-ups, both aniline 6 and inorganic salts partitioned into the aqueous layer. 6 could be back-extracted into an organic phase using DCM and isolated cleanly as a brown oil. To avoid tedious extractions and minimize solvent use, we questioned whether 6 could instead be isolated as a salt. Consequently, the aniline was tested on a 10 μmol scale against 12 sulfonic acids and 2 solvents: In six of these trials, salt precipitation was observed. (See the Supporting Information for details.) Of those hits, TsOH was chosen for its ability to reject both residual substrate and the linear isomer. With these results in hand, the optimized Negishi cross-coupling procedure and isolation were performed on a 30 g scale, achieving 89% isolated yield and delivering salt 7 as a white solid with 99 LCAP and 99:1 b:l ratio (Scheme 1).
This activity model should accelerate future catalyst selection in heteroaryl-alkyl cross-couplings relevant to drug development.
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EXPERIMENTAL SECTION
Materials and Methods. Unless otherwise stated, reactions were performed under a nitrogen atmosphere using Sigma-Aldrich SureSeal solvents. 1.0 M iPrZnBr in THF was purchased from Rieke Metals. 2.0 M iPrMgCl in THF and 1.9 M ZnCl2 in MeTHF were purchased from Sigma-Aldrich. Initial catalyst screening was performed using a Sigma-Aldrich KitAlysis CN coupling kit (Part Number KitalysisCN). Xantphos Pd G3 was purchased from Johnson Matthey (Pd187), EtCPhos Pd G3 was purchased from Strem, and PEPPSI IHeptCl was purchased from Total Synthesis. Unless otherwise stated, chemicals and reagents were used as received. Reactions were monitored by thin-layer chromatography using EMD/Merck silica gel 60 F254 precoated plates (0.25 mm) and were visualized by UV staining. Flash column chromatography was performed using a Teledyne Isco Combi-Flash system and RediSep normal-phase silica flash columns. 1H and 13C NMR spectra were recorded on a Bruker 400 apparatus (at 400 and 101 MHz, respectively) and are reported relative to internal CHCl3 (1H, δ 7.26) and CDCl3 (13C, δ 77.0) or DMSO (1H, δ 2.50) and d6-DMSO (13C, δ 39.5). Data for 1H NMR spectra are reported as follows: chemical shift (δ) (multiplicity, coupling constant (Hz), integration). Multiplicity and qualifier abbreviations are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, app = apparent. High-resolution mass spectra (HRMS) were acquired using a Thermo Scientific QExactive high-resolution mass spectrometer with an HESI source in positive mode. Analytical ultra-high-performance liquid chromatography (UHPLC) was performed with an Agilent 1100 series UHPLC. Preliminary Catalyst Screen. Catalyst screening was performed using a KitAlysis CN coupling plate (Sigma-Aldrich). The plate contained 12 preweighed catalysts (1 μmol each, 0.1 equiv) and stir bars. The plate was transferred to a nitrogen-filled glovebox. To each reaction vial was added 85 μL of 0.12 M bromopyridine solution in THF (10 μmol, 1 equiv), followed by 150 μL of 1 M iPrZnBr in THF (15 μmol, 1.5 equiv). The vials were sealed and stirred at 30 °C for 4 h. The plate was removed from the glovebox, and the reactions were quenched with 0.4 mL of 10 mM biphenyl in MeOH. The reactions were stirred for 5 min, and any solids were allowed to settle for 15 min. UHPLC samples were prepared by diluting a 25 μL aliquot with 800 μL of MeOH. Substrate Screen. 0.03 M stock solutions of Xantphos Pd G3 (C1), CPhos Pd G3 (C2), and PEPPSI IHept-Cl (C3) in THF were prepared. 1.0 M stock solutions of halide substrates in THF were prepared; they were then doped with biphenyl as an internal standard. The substrate solutions were held at 45 °C to prevent precipitation. 1.0 M iPrZnBr in THF from Rieke Metals or 0.5 M nPrZnBr in THF
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CONCLUSIONS A reactivity model for three aryl−alkyl coupling catalysts has been presented. Xantphos Pd G3 delivers exceptional b:l selectivity for activated heteroaryl scaffolds common in the pharmaceutical industry. The process can be run under low catalyst loading and mild conditions, and the precatalyst and organometallic reagent are readily available on a large scale. The catalyst also shows promise for selective functionalization of complex molecules bearing two halides. Its fitness toward large-scale applications was demonstrated on a 30 g scale following preliminary process optimization. Our analysis also showed that PEPPSI IHept-Cl was the most general of the catalysts tested and maintained high selectivity for both sterically crowded substrates and electron-deficient arenes. D
DOI: 10.1021/acs.organomet.8b00590 Organometallics XXXX, XXX, XXX−XXX
Organometallics
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from Sigma-Aldrich was used without any modification. The reactions were performed in a nitrogen-filled glovebox using a Freeslate Jr. liquid handling system. The plate design for the reaction screen is shown in Figure S2. Each reaction vial was dosed with 0.45 mL of i PrZnBr or 0.9 mL of nPrZnBr (0.45 mmol, 1.5 equiv). 0.1 mL of catalyst stock solution (0.003 mmol, 0.01 equiv) was added to each reaction, followed by 0.3 mL of electrophile stock solution (0.3 mmol). The reactions were stirred at 300 rpm and ambient temperature for 4 h. Stirring was stopped, and solids were allowed to settle. A 25 μL aliquot was removed and diluted with 1 mL of 3:1 MeOH/H2O. The sample was filtered and analyzed by UHPLC. 30 g Synthesis of 7 (Scheme 1). A 1 L jacketed reactor with overhead stirring was inerted with nitrogen. 2.0 M iPrMgCl in THF (190 mmol, 1.3 equiv) was added to the reactor. The jacket temperature was set to 20 °C, and the solution was stirred at 600 rpm. To the solution was added 1.9 M ZnCl2 in MeTHF (95 mmol, 0.65 equiv) over 25 min. The reaction formed a thick slurry, and the jacket temperature was increased to 30 °C. Xantphos Pd G3 (0.74 mmol, 0.005 equiv) was added as a slurry in 10 mL of THF using 5 mL of THF to rinse. The thick slurry was stirred at 30 °C for 1 h. 2-Bromo4-methyl-pyridin-3-amine (5, 30 g, 148 mmol, 92 wt %) was diluted with THF (60 mL) and added dropwise via syringe pump over 45 min. An exotherm occurred, and the slurry thinned over the course of the addition. The reaction was stirred at 30 °C for an additional 2 h. Reaction completion was confirmed by UHPLC (96 LCAP product, 32:1 b:l). The reaction mixture was quenched by the careful addition of 1 M HCl (90 mL), and the reaction was stirred until the inorganic salts had dissolved in the aqueous layer. An exotherm was observed. Sat. aq. NH4Cl (90 mL) was added, and the reaction was stirred. The reaction was pH-adjusted by adding 5 M NaOH (72 mL) over four portions with vigorous stirring. The pH was confirmed to be 7.5 to 8. The aqueous layer was removed. The organic layer was distilled down to 90 mL (55 °C, 230 Torr). Some inorganic salts precipitated. The mixture was azeotroped with MeTHF and then filtered through a fine frit using MeTHF to rinse. The filtrate was added to a clean 1 L jacketed reactor and adjusted with MeTHF to a total of 200 mL. The jacket was set to 50 °C. TsOH (190 mmol, 1.3 equiv, 90 wt %) was added in one portion, and the reaction was stirred vigorously for 1 h. The jacket temperature was reduced to 20 °C over 2 h. The resulting slurry was stirred overnight. The slurry was filtered through a medium frit and washed with MeTHF. The solid was dried overnight over a stream of air, yielding 43.45 g monoacid salt (89% yield, 99 LCAP, 99:1 b:l). 1H NMR (400 MHz, d6-DMSO) δ 14.14 (br s, 1H), 7.88 (d, J = 5.8 Hz, 1H), 7.53−7.48 (m, 3H), 7.12 (d, J = 7.9 Hz, 2H), 6.11 (br s, 2H), 3.50 (spt, J = 6.9 Hz, 1H), 2.32 (s, 3H), 2.28 (s, 3H), 1.28 (d, J = 7.1 Hz, 6H). 13C NMR (101 MHz, d6-DMSO) δ 145.4, 142.7, 141.8, 139.2, 137.8, 128.1, 127.6, 125.5, 125.4, 26.8, 20.7, 19.6, 18.57. HRMS calcd for C9H14N2 [free base + H]+ 151.1230, found 151.1231.
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ACKNOWLEDGMENTS We are grateful to Dr. Daniel Griffin for helpful discussions and assistance with operating the Freeslate Jr. Helen Yan is thanked for assistance with mass spectrometry.
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REFERENCES
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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.organomet.8b00590.
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Article
Experimental procedures, characterization, and spectral data for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Alan H. Cherney: 0000-0001-7440-6634 Steven M. Mennen: 0000-0003-1905-5530 Notes
The authors declare no competing financial interest. E
DOI: 10.1021/acs.organomet.8b00590 Organometallics XXXX, XXX, XXX−XXX
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Organometallics with Aryl and Alkenyl Triflates and Nonaflates. Angew. Chem., Int. Ed. 2018, 57, 1982−1986. (11) Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. Rings in Drugs. J. Med. Chem. 2014, 57, 5845−5859. (12) For a review on the cross-coupling of heteroarenes, see: Slagt, V. F.; de Vries, A. H. M.; de Vries, J. G.; Kellogg, R. M. Practical Aspects of Carbon−Carbon Cross-Coupling Reactions Using Heteroarenes. Org. Process Res. Dev. 2010, 14, 30−47. (13) Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Reek, J. N. H. Wide Bite Angle Diphosphines: Xantphos Ligands in Transition Metal Complexes and Catalysis. Acc. Chem. Res. 2001, 34, 895−904. (14) For the related use of an informer library, see: Kutchukian, P. S.; Dropinski, J. F.; Dykstra, K. D.; Li, B.; DiRocco, D. A.; Streckfuss, E. C.; Campeau, L. C.; Cernak, T.; Vachal, P.; Davies, I. W.; Krska, S. W.; Dreher, S. D. Chemistry Informer Libraries: A Chemoinformatics Enabled Approach to Evaluate and Advance Synthetic Methods. Chem. Sci. 2016, 7, 2604−2613. (15) For an example of Xantphos in a regioselective cross-coupling, see: Ashcroft, C. P.; Fussell, S. J.; Wilford, K. Catalyst Controlled Regioselective Suzuki Cross-Coupling of 2-(4-bromophenyl)-5Chloropyrazine. Tetrahedron Lett. 2013, 54, 4529−4532. (16) Nonpyridyl heterocycles were also briefly examined: High selectivity was achieved with 2-bromopyrimidine, whereas 2bromoquinoline was not soluble under the reaction conditions. (17) A preliminary study of Pd sources showed that Xantphos Pd G3 provided better results than premixing Pd(OAc)2 or Pd2(dba)3 with Xantphos. Additionally, conducting the reaction at 50 °C instead of 30 °C eroded the selectivity from 30:1 b:l to 15:1 b:l. (18) (a) Achonduh, G. T.; Hadei, N.; Valente, C.; Avola, S.; O’Brien, C. J.; Organ, M. G. On the Role of Additives in Alkyl-Alkyl Negishi Cross-Couplings. Chem. Commun. 2010, 46, 4109−4111. (b) McCann, L. C.; Hunter, H. N.; Clyburne, J. A.; Organ, M. G. Higher-Order Zincates as Transmetalators in Alkyl-Alkyl Negishi Cross-Coupling. Angew. Chem., Int. Ed. 2012, 51, 7024−7027. (c) McCann, L. C.; Organ, M. G. On the Remarkably Different Role of Salt in the Cross-Coupling of Arylzincs From That Seen With Alkylzincs. Angew. Chem., Int. Ed. 2014, 53, 4386−4389. (19) Manley, J. M.; Kalman, M. J.; Conway, B. G.; Ball, C. C.; Havens, J. L.; Vaidyanathan, R. Early Amidation Approach to 3-[(4amido)pyrrol-2-yl]-2-Indolinones. J. Org. Chem. 2003, 68, 6447− 6450.
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DOI: 10.1021/acs.organomet.8b00590 Organometallics XXXX, XXX, XXX−XXX
