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Up the Periodic Table and to the Bench: Practical organometallic chemistry for medicinal and process chemists

By Ryan Woltornist

Organometallic reagents and the synthetic methodologies that accompany their development are directly influenced by industrial needs. Without direct utility in industry, organometallic-based transformations are esoteric at best and likely to be impractical for the synthetic community at large. If so, the question that should be asked is what are industrial chemists—specifically medicinal and process chemists—looking for? A thorough analysis of the medicinal chemistry literature by Boström et al. found three criteria of paramount importance: (1) readily available reagents, (2) ease of synthesis (simplicity of reaction setup), and (3) diverse functional group tolerance[1]. Though these guidelines have been dictated by industrial chemists, the same general rules apply in academia.

In certain cases, the organometallic community has already begun the push to satisfy the tenet related to commonplace reagents. This is being achieved by using more abundant metals such as higher row main group metals and first row transition metals. Not only are the costs lower[2], but generally they display low toxicity, which is of the upmost importance in the development of pharmaceuticals[3–5].  Specifically, 3d transition metals have taken center stage with the work being done in the realm of C–H functionalization having direct application in the development of pharmacutials [6–8]. Nevertheless, tedious organometallic syntheses requiring specialized equipment causes the barrier to adoption insurmountable [1]. For organometallic chemistry to benefit all practitioners, reaction setups must move out of the glove box and on to the benchtop. Benchtop preparations from readily available, off–the–shelf starting materials is a very realistic goal.

Main group metals have their place in the future of organometallic chemistry as well. A prime example of an organometallic reagent that satisfies the criteria listed above is sodium diisopropylamide (NaDA). Although lithium diisopropylamide (LDA) is used hundreds if not thousands of times daily, only a dozen reports on NaDA have appeared in the literature since the first report by Levine and co-workers in 1960 [9]. It is difficult to explain with confidence this dearth of publications, but the essence of the problem is organosodium reagents were said to be “limited in part due to competition from organolithium compounds” and that they are “poorly soluble”. Our group has found that using sodium dispersion in toluene, simple trialkylamines (NR3), isoprene, and diisopropylamine—all readily available starting materials—generates highly concentrated (1.0 M) solutions of NaDA/NR3 on the benchtop in minutes that can be stored for months with refrigeration [10]. Recently, an unpublished benchtop prep to generate solutions of NaDA/tetrahydrofuran (THF) will likely further pique the interest of synthetic chemists. Since the publication of the benchtop NaDA prep in 2016 the synthetic community seems to have caught on [11–16], prompting one author to claim that “sodium is coming of age”[17]. We agree and feel that organosodium chemistry is about to explode.

References:
(1) Boström, J.; Brown, D. G.; Young, R. J.; Keserü, G. M. Expanding the Medicinal Chemistry Synthetic
Toolbox. Nat. Rev. Drug Discov. 2018, 17, 709–727.
(2) http://mineralprices.com/default.aspx#rar, http://www.infomine.com/investment/metal-prices/ and
http:/original.metal. com/metals/productinfo/201102250232, accessed on 08/12/2019.
(3) Holubek, J. C. Spectral data and physical constants in Alkaloids; Academie: Prague, 1972; Vol VII.
(4) Cheeke, P. R. Symposium on Pyrrolizidine (Senecio) Alkaloids : Toxicity, Metabolism, and Poisonous Plant
Control Measures: The Proceedings of a Symposium Held at Oregon State University, February 23 and 24,
1979. Nutrition Research Institute, Oregon State University 1979.
(5) Ysart, G.; Miller, P.; Crews, H.; Robb, P.; Baxter, M.; L’Argy, C. De; Lofthouse, S.; Sargent, C.; Harrison,
N. Dietary Exposure Estimates of 30 Elements from the UK Total Diet Study. Food Addit. Contam. 1999,
16, 391–403.
(6) Gandeepan, P.; Müller, T.; Zell, D.; Cera, G.; Warratz, S.; Ackermann, L. 3d Transition Metals for C–H
Activation. Chem. Rev. 2018, 119, 2192–2452.
(7) Zhao, J.; Nanjo, T.; de Lucca, E. C.; White, M. C. Chemoselective Methylene Oxidation in Aromatic
Molecules. Nat. Chem. 2019, 11, 213–221.
(8) White, M. C.; Zhao, J. Aliphatic C-H Oxidations for Late-Stage Functionalization. J. Am. Chem. Soc. 2018,
140, 13988–14009.
(9) Raynolds, S.; Levine, R. The Synthesis of Nitrogen-Containing Ketones. VIII. The Acylation of 3-Picoline,
4-Picoline and Certain of Their Derivatives. J. Am. Chem. Soc. 1960, 82, 472–475.
(10) Ma, Y.; Algera, R. F.; Collum, D. B. Sodium Diisopropylamide in N,N-Dimethylethylamine: Reactivity,
Selectivity, and Synthetic Utility. J. Org. Chem. 2016, 81, 11312–11315.
(11) Weidmann, N.; Ketels, M.; Knochel, P. Sodiation of Arenes and Heteroarenes in Continuous Flow. Angew.
Chem. Int. Ed. 2018, 57, 10748–10751.
(12) Ma, Y.; Woltornist, R. A.; Algera, R. F.; Collum, D. B. Aryl Carbamates: Mechanisms of Orthosodiations
and Snieckus–Fries Rearrangements. J. Org. Chem. 2019, 84, 9051–9057.

(13) Algera, R. F.; Ma, Y.; Collum, D. B. Sodium Diisopropylamide in Tetrahydrofuran: Selectivities, Rates, and
Mechanisms of Alkene Isomerizations and Diene Metalations. J. Am. Chem. Soc. 2017, 139, 11544–11549.
(14) Majhi, J.; Turnbull, B. W. H.; Ryu, H.; Park, J.; Baik, M.-H.; Evans, P. A. Dynamic Kinetic Resolution of
Alkenyl Cyanohydrins Derived from α,β-Unsaturated Aldehydes: Stereoselective Synthesis of E –
Tetrasubstituted Olefins. J. Am. Chem. Soc. 2019, 141, 11770–11774.
(15) Pang, J. H.; Ong, D. Y.; Watanabe, K.; Takita, R.; Chiba, S. Leaving Group Ability in Nucleophilic
Aromatic Amination by Sodium Hydride–Lithium Iodide Composite. Synthesis (Stuttg). 2019.
https://doi.org/10.1055/s-0039-1690010.
(16) Asako, S.; Nakajima, H.; Takai, K. Organosodium Compounds for Catalytic Cross-Coupling. Nat. Catal.
2019, 2, 297–303.
(17) Wong, H. N. C. Is Sodium Finally Coming of Age? Nat. Catal. 2019, 2, 282–283.

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