Metal Catalyzed Synthesis of Dihydropyridobenzodiazepines

May 16, 2018 - they recently have generated interest as inhibitors of IDH3 mutant enzymes and as potential agonists for bombesin receptor subtype-34 o...
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Metal Catalyzed Synthesis of Dihydropyridobenzodiazepines Matthew L. Maddess* and Chaomin Li Process Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States

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S Supporting Information *

ABSTRACT: A versatile synthesis of dihydropyridobenzodiazepines that proceeds via a palladium-catalyzed C−N coupling and catalytic hydrogenation cascade is reported. The intermediate 2anilinonicotinaldehydes may be efficiently protected to ultimately afford N6 differentiated dihydropyridobenzodiazepines, which facilitates further elaboration.

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s a general class, benzodiazepines have enjoyed remarkable success as a privileged scaffold in the construction of pharmacologically active substances that improve human health.1,2 The subsets of dihydropyridobenzodiazepines have received less attention historically; however, they recently have generated interest as inhibitors of IDH3 mutant enzymes and as potential agonists for bombesin receptor subtype-34 or vasopressin V2 receptors.5 Most existing routes to functionalized dihydropyridobenzodiazepines involve condensation of a 2-halo-nicotinic acid derivative with a dianiline followed by lactam reduction and subsequent derivatization of the heterocyclic scaffold (Scheme 1, top).4,5 While concise, this approach has suffered from a number of drawbacks, for instance, control of regiochemistry, moderate yields associated with lactam reduction, generally poor organic solubility, associated challenges with purification, Scheme 1. Strategies for Construction of Dihydropyridobenzodiazepines

Figure 1. Parameter trends in the preparation of 2.

and finally, potential regiochemical issues related to selective functionalization at either nitrogen of the central diazepine. In an effort to develop a general method that effectively addresses all of the challenges mentioned above, we have explored a C− N coupling/reductive cascade approach to access the desired dihydropyridobenzodiazepines. In principle, the cross-coupling partners are expected to be highly activated and could be used Special Issue: The Roles of Organometallic Chemistry in Pharmaceutical Research and Development Received: May 16, 2018

© XXXX American Chemical Society

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DOI: 10.1021/acs.organomet.8b00322 Organometallics XXXX, XXX, XXX−XXX

Communication

Organometallics Table 1. Preparation of Boc Protected 2-Anilinonicotinaldehydes (Isolated Yields Reporteda−d)

Table 2. Reductive Cascade Affording N6 Differentiated Dihydropyridobenzodiazepines (Isolated Yields Reporteda−c)

a

Approach A. b2-Anilino-nicotinaldehyde isolated. cApproach B1. Approach B2.

d

a

Scheme 2. Preparation of Benzyl Protected 2-Anilinonicotinaldehydes

c

H2 (1 atm), Pd/C (10 mol %). bH2 (1 atm), Pt−V/C (10 mol %). Over-reduction products observed.

nicotinaldehydes with the appropriate electrophilic or nucleophilic coupling partners. For these high-throughput (HTE) screens,10 palladium precatalysts11 were ideal, offering advantages of stability, simplicity on weighing, and activity, which translated to a robust data set. Analysis of the crude reaction mixtures for the presence of product relative to a standard amount of biphenyl (IS) indicated numerous catalyst systems that were efficient at effecting the desired transformation. As development of robust conditions with a broad scope was our primary objective, data were analyzed in a holistic way to explore trends within, and across, the three systems (Figure 1).12 The Pd catalyst system appeared to have the most dramatic effect on performance with those incorporating RuPhos, BINAP, NiXantPhos, and XantPhos as ligands being most successful. Generally, cesium carbonate provided higher assay yields to potassium phosphate while solvents were roughly equivalent (slight trend was observed: THF > tAmylOH > dioxane > DMAc). With respect to the latter, the ability to telescope crude mixtures of 2 through relevant N11 functionalization was taken into account. Preliminary investigation revealed a Boc

in either sense (Scheme 1, bottom, A or B) to impart considerable flexibility to the approach, leveraging a variety of commercially available starting materials.6 The intervening 2anilino-nicotinaldehydes with the eventual N6 nitrogen masked as a nitro group would allow for selective functionalization at this stage.7 Finally, numerous approaches are available to effect a reductive cascade8 that results in nitro group reduction,9 imine formation, and a subsequent reduction to the desired differentiated heterocycle (Scheme 1, bottom panel). A variety of catalyst systems, solvents, and bases were examined for the construction of 2-((2-nitrophenyl)amino)nicotinaldehyde (2) from either 2-amino- (1) or 2-halo- (3) B

DOI: 10.1021/acs.organomet.8b00322 Organometallics XXXX, XXX, XXX−XXX

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Organometallics

and 6h).17 In these instances there were no clear trends related to electronic or steric factors (Table 2). While not explored for all substrates, additional optimization on solvent, temperature, and pressure is expected to be fruitful. For example, screening conditions for 6b revealed significantly shorter reaction times (0.5 to 2 h) could be achieved at 200 psi of H2 and 50 °C with equivalent or better reaction performance. Pure alcohol solvents (EtOH or TFE), as well as 1:1 mixtures of EtOAc/AcOH, were competent alternatives to the 1:2 EtOAc/MeOH mixture used in Table 2 providing additional flexibility. For substrates (e.g., 6c and 6m) that contained halides, platinum doped with vanadium18 was employed in place of Pd/C to minimize unwanted C−X reduction, which was notably more prevalent with bromides than chlorides. Other doped platinum systems (with Bi, Al2O3, CuO, FeO, Ru, or S) were investigated but were found to be inferior to the Pt−V mixture. Overall, the reported approach provided good to excellent yields for all substrates explored, affording a diverse set of pharmacologically relevant building blocks (Table 2). In conclusion, concise catalytic entry to N11 Boc protected dihydropyridobenzodiazepines has been developed. The above methodology is versatile, robust, scalable, and provides differentiated building blocks which should be of interest to medicinal chemistry programs.

group was efficiently introduced at N11 in THF. With these results on hand, further optimization led to the selection of the preferred conditions represented in Table 1 for the synthesis of protected precursors (4) to the desired dihydropyridobenzodiazepines. In addition to reaction performance, factors associated with availability and cost influenced the decision to select the XantPhos Pd2(dba)3 system to support possible larger scale work. Interestingly, this was not an obvious choice based upon the initial screening results as the XantPhos 3G system had not performed well with approach A in THF (2/IS = 2.36, Figure 1). Replacement of the precatalyst with the separated Pd and ligand combination was considered the source of the discrepancy given both dba and carbazole have been reported to affect catalytic processes.13 However, repeat experiments on a millimolar scale (Approach A, XantPhos 3G, THF/Cs2CO3) gave full conversion and equivalent isolated yield to that in Table 1, indicating the initial screening result was a false negative.10a As these are difficult to avoid entirely in an HTE format, exploring trends (vide supra) in large data sets can be an effective strategy in selecting followup conditions for iterative optimization. These optimized conditions translated across a range of substrates to afford the desired C−N Boc protected products in good to excellent yields (Table 1). The sequence tolerates a high degree of functional group variety. Electronic and steric perturbations are tolerated, and the introduction of heterocycles is permitted. As use of a slight excess of the electrophilic partner tended to give superior results, most examples were intentionally exemplified using the more expensive 2-amino nicotinaldehydes as the limiting reagent (i.e., Table 1: approach A). However, the reverse coupling approaches (B1 and B2) were comparably effective when a direct evaluation (4b) was made. In some instances, approach B was superior (4c), demonstrating that a judicious choice of coupling partners can be made to minimize undesired C−N regioisomers.14 Furthermore, the commercial availability of starting materials at times made the 2-halonicotinaldehyde entry preferable, validating the predicted flexibility of the approach (e.g., 4n).15 A streamlined, one-pot process was often operationally advantageous and typically gave superior isolated yields over 2 steps than when the 2-anilino-nicotinaldehydes were isolated (e.g., 4a and 4h). This is attributed to rather low solubility of the unprotected C−N coupled products (2) and at times suboptimal performance on silica gel during purification.16 Boc protection, using either isolated intermediates, or crude reaction mixtures, was efficient and usually complete in 1 h with the exception of sterically encumbered substrates (e.g., 4m and 4q), which were left to react for 14 h. Alkylation was also explored to provide access to benzylated derivatives (5) as an orthogonal alternative to the Boc substrates described above. This was achieved by subjecting isolated 2-anilino-nicotinaldehydes in DMF to benzyl bromide with Cs2CO3 as a base (Scheme 2). Having established a robust C−N coupling protocol, we focused our efforts toward realization of the reductive cascade to furnish the final N-differentiated dihydropyridobenzodiazepines. Of the myriad reduction conditions known9 to induce this sequence, heterogeneous hydrogenation using Pd/C was the most successful. As expected, intermediate aniline and cyclized imine intermediates were observed during the reaction. Typically, these would convert to the desired product under elongated reaction times (∼14 h). However, a number of substrates failed to reach complete conversion (e.g., 6f, 6g,

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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.organomet.8b00322. Experimental procedures, full screening results, tabulated characterization data, and copies of NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Matthew L. Maddess: 0000-0002-7273-528X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to thank Bruce Adams and Josep Saurı ́ for NMR support, Simon Barrett and Donald Sperbeck for reaction screening support, and Wilfredo Pinto and Adam Beard for HRMS analysis.

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REFERENCES

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butylphosphino Biaryl Ligands. Org. Lett. 2013, 15, 2876−2879. (d) Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Design and preparation of new palladium precatalysts for C−C and C−N crosscoupling reactions. Chem. Sci. 2013, 4, 916−920. (e) Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. A New Class of Easily Activated Palladium Precatalysts for Facile C−N Cross-Coupling Reactions and the Low Temperature Oxidative Addition of Aryl Chlorides. J. Am. Chem. Soc. 2008, 130, 6686−6687. For reviews, see: (f) Bruneau, A.; Roche, M.; Alami, M.; Messaoudi, S. 2-Aminobiphenyl Palladacycles: The “Most Powerful” Precatalysts in C−C and C−Heteroatom Cross Couplings. ACS Catal. 2015, 5, 1386−1396. (g) Li, H.; Johansson Seechurn, C. C. C.; Colacot, T. J. Development of Preformed Pd Catalysts for Cross-Coupling Reactions, Beyond the 2010 Nobel Prize. ACS Catal. 2012, 2, 1147−1164. (12) For full results for the C−N coupling screen(s), see the Supporting Information. (13) (a) Janusson, E.; Zijlstra, H. S.; Nguyen, P. P. T.; MacGillivray, L.; Martelino, J.; McIndoe, J. S. Real-time analysis of Pd2(dba)3 activation by phosphine ligands. Chem. Commun. 2017, 53, 854−856. (b) Fairlamb, I. J. S.; Kapdi, A. R.; Lee, A. F.; McGlacken, G.; Weissburger, F.; de Vries, A. H. M.; Schmieder-van de Vondervoort, L. Exploiting Noninnocent (E,E)-Dibenzylideneacetone (dba) Effects in Palladium(0)-Mediated Cross-Coupling Reactions: Modulation of the Electronic Properties of dba Affects Catalyst Activity and Stability in Ligand and Ligand-Free Reaction Systems. Chem. - Eur. J. 2006, 12, 8750−8761. Also, see footnote 8: (c) Park, N. H.; Vinogradova, E. V.; Surry, D. S.; Buchwald, S. L. Design of New Ligands for the Palladium-Catalyzed Arylation of α-Branched Secondary Amines. Angew. Chem., Int. Ed. 2015, 54, 8259−8262. (14) A significant amount of the meta-coupled analogue to 4c was observed in the reaction mixture using approach A. In such cases where competing C−N coupling is problematic, placement of the complicating halide on the nucleophilic partner can resolve (e.g., see the SI for 2c and 2m). (15) 2-Methoxy-5-nitro-4-pyridinamine is lower cost and has more commercial sources than the corresponding four halo analogues. (16) Inefficiently large volumes (>40) were often required to solubilize representative 2-anilino-nicotinaldehydes (e.g., 2b) during workup. Streaking during chromatography was common; in addition, clogging due to crystallization on the silica gel column occurred in some cases. (17) If stalled, varying amounts of reduced but uncyclized aniline as well as the cyclized imine was observed. (18) 3% Pt doped with 0.6% vanadium on activated carbon was obtained from Evonik.

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DOI: 10.1021/acs.organomet.8b00322 Organometallics XXXX, XXX, XXX−XXX