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Practical and Regioselective Synthesis of C4-Alkylated Pyridines Jin Choi†, Gabriele Laudadio†, Edouard Godineau††, Phil S

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Practical and Regioselective Synthesis of C4-Alkylated Pyridines Jin Choi†, Gabriele Laudadio†, Edouard Godineau††, Phil S Practical and Regioselective Synthesis of C4-Alkylated Pyridines Jin Choi†, Gabriele Laudadio†, Edouard Godineau††, Phil S. Baran*† † Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, California 92037, United States ††Process Research, Syngenta Crop Protection, Schaffhauserstrasse 101, CH-4332 Stein, Switzerland ABSTRACT: The direct position-selective C–4 alkylation of pyr- Hong group reported a radical-type addition using N-sulfon- idines has been a longstanding challenge in heterocyclic chemistry, amidopyridinium species10 using alkyl bromide donors requiring particularly from pyridine itself. Historically this has been ad- photochemical initiation and super stoichiometric amounts of an 11 dressed using pre-functionalized materials to avoid overalkylation expensive silane [(TMS)3SiH]. While this is an important prece- and mixtures of regioisomers. This study reports the invention of a dent it could not be employed easily on process scale as three steps simple maleate-derived blocking group for pyridines that enables are needed to install the blocking group (1. N-amination using hy- exquisite control for Minisci-type decarboxylative alkylation at C– droxylamine-O-sulfonic acid, 2. tosylation, and 3. methylation with 4 that allows for inexpensive access to these valuable building Meerwein’s salt along with 1 column purification, 1 recrystalliza- blocks. The method is employed on a variety of different pyridines tion). The Buchwald group reported a Cu-catalyzed, selective C4 and carboxylic acid alkyl donors, is operationally simple, scalable, functionalization of pyridine with styrenes without a covalent and is applied to access known structures in a rapid and inexpensive blocking group, via a novel intramolecular rearrangement mecha- fashion. Finally, this work points to an interesting strategic depar- nism mediated by a pyridine coordinated copper species.7e,7h ture for the use of Minisci chemistry at the earliest possible stage Herein we disclose a highly practical method featuring on a new (native pyridine) rather than current dogma that almost exclusively blocking group based on a simple fumarate backbone (6a) enabling employs Minisci as a late-stage functionalization technique. classic Minisci decarboxylative alkylations to take place with ex- quisite selectivity at C–4 (Figure 1C) under acid-free conditions. Emblematic of this advance is the preparation of 4-cyclohexylpyr- idine (8) which cannot be accessed from pyridine in a synthetically The power of C–H functionalization logic in the context of syn- useful yield and as a mixture of isomers under four different thesizing heteroaromatic structures is undeniable.1 Its increasing Minisci-type conditions. utility in discovery and medicinal chemistry contexts is a testament A. Regioselective C4-Alkylation of Pyridines: An Unsolved Challenge to its utility in late-stage derivatization enabling structure activity 2 H selectivity R X relationships to be rapidly explored. In particular, the venerable 4 cross coupling Minisci reaction and its many variants have long been recognized issue as a way to bypass pre-functionalized heterocycles.3 Just as the H 2 N N N Friedel-Crafts reaction is commonplace for electron rich arene R or R 1 2 functionalization via electrophilic substitution, free radicals can re- B. Literature Precedent for Selective C-4 Alkylation act with electron deficient heterocycles by capitalizing on innate tBu R = reactivity.4 In cases where a heterocycle has multiple sites to inter- OR RO Al Me OMs N cept a free radical, mixtures often result which can be useful in a N Me N Me Ts Me discovery setting but is problematic when a singular regiochemical tBu [Hong, 2019] 5 outcome is desired (e.g. process scale). For example, simple 4-al- [Nakao, 2010] [Fier, 2019] • Radical mechanism [C–2 blocking • Catalytic • 3 examples • Alkyl bromides kylated pyridines (1, Figure 1A) are inaccessible using Minisci group] • Olefin donors (PhMgBr, Et2Zn, • 2 equiv (TMS)3SiH chemistry if a single regioisomer is desired. In such cases, prefunc- • Glove box dimethylmalonate) • Photochemical tionalization is necessary and the logical synthon is halopyridine 2. C. Comparison of Reactivity and Regioselectivity with Pyridine This conundrum has rendered the early-stage application of Minisci [classical Minisci or Minisci-type reaction] chemistry on pyridine and mono-substituted pyridines rare in me- Radical CyCO2H CyBF3K CyCO2NPthl dicinal chemistry and, to our knowledge, non-existent on process N Precursors (3) (4) (5) N Cy 6 or scale. A recent collaborative program within the agrochemical in- [from pyridine] 26% 11% 14% >5% 7, C2 dustry brought to our attention the need for a simple and inexpen- C2:C4 1:2.3 1:1 1:2.8 1:1 Cy sive solution to this unmet challenge in pyridine alkylation for N [from 6a] 81% 39% 42% 37% which available methods were not applicable. To be sure, several [ref 12a] [ref 12b] [ref 12c] [ref 12d,e] EtO2C N attempts to solve this problem from unfunctionalized starting ma- [C-4 exclusive, this work] [H+ free Minisci] 8, C4 terials have appeared over the past decade (Figure 1B) mostly 6a CO2Et based on blocking competitive C–2 sites using transient or cova- Figure 1. (A) An unsolved challenge in the field of Minisci reac- lently linked species at the pyridine nitrogen.7 Nakao’s pioneering tion. (B) Literature precedent. (C) Comparison experiment with studies using bulky Al-based Lewis-acids in an elegant hydroary- pyridine lation process is limited to olefin donors and must be performed in a glove box.8 The Fier group at Merck invented clever oxime-based Tactically, scalable access to valuable structures such as 8 (81% pyridinium species that could be employed in three examples of C– isolated yield from 6a) can now be enabled with a dramatic reduc- C bond formation with carbon-based nucleophiles.9 Finally, the tion in cost. From a strategic perspective, this work opens a new dimension of retrosynthetic logic for use of the Minisci transform or Sonogashira,17b respectively) followed by reduction (ca. at an early rather than late stage. $530/g13c). Similarly, pyridine 16 can be accessed via reduction of 18 Guided by colleagues at Syngenta (E.G.) several criteria needed the Heck product of 4-vinylpyridine and an aryl iodide. to be met for a practical blocking group (BG) design, such as: (1) Numerous secondary carboxylic acids were employed to access derivation from feedstock materials (ca. $5/mole), (2) simple in- such pyridines with high simplicity when placed in context. For ex- stallation and removal, (3) high stability, ease of handling, and sol- ample, pyridine 8 has been prepared multiple times leading either ubility in multiple solvents, and most critically, (4) complete regi- to mixtures (e.g., Figure 2B) or requiring pre-functionalized pyri- ochemical control to avoid the need for any chromatography. To- dines (ca. $584/g13d).19 Similarly, pyridine 18 has been accessed wards this end, multiple BGs were explored with most falling into from 4-bromopyridine through photochemical and electrochemical one of two categories (Figure 2A): (1) simple BG installation with reductive couplings or by employing Hong’s BG (Figure 1B) and a either modest or low reactivity under Minisci conditions (BG1, 2, Hantzsch ester radical precursor10b (ca. $150/g13e). Pyridine 21 has 4, 6) or (2) difficulty in forming a stable BG adduct. After extensive been accessed either via cross coupling/Hydrogenation20a or C4-se- exploration, BG10 emerged as an ideal candidate satisfying all of lective Grignard addition using TBSOTf to generate a transient BG the criteria laid out above. BG9 was the only other moderately suc- and reoxidation20b (ca. $100/g13b). Cyclopropyl containing pyridine cessful one however it exhibited reduced reactivity towards Minisci 23 was accessed either from 4-bromo or 4-Bpin pyridine via Suzuki addition. The preparation of pyridinium 6a with BG10 could be or Grignard addition/rearomatization (ca. $226/g13a).21 The trivial prepared through a simple, chromatography-free, two-step se- cyclohexanone pyridine 25 has only been accessed in a controlled quence starting from commodity materials (pyridine and maleic fashion using multistep routes with protecting groups and FG ma- acid) followed by esterification. The structure of pyridinium 6a was nipulations (ca. $871/g13f).22 confirmed by X-ray crystallography and contained the ethyl sul- Many of the quaternary center containing C-4 alkylated pyri- fonate as a counter-anion. This crystalline salt represents a straight- dines (derived from tertiary carboxylic acids) prepared here are forward gateway to a variety of C–4 alkylated pyridines (vide infra) new (29-33) and are likely desirable starting materials for medici- and has been commercialized by Sigma-Aldrich (catalog # nal chemistry programs. Of the known alkylated pyridines in this ALD00619). series, two were prepared as mixtures of regioisomers using radical chemistry (26 and 28)23,24 or via Minisci addition to 4-cyano- A. A Fumarate-Derived Blocking Group For Minisci: Discovery pyridine.25 + H -free Minisci (AgNO3, (NH4)2S2O8, 2 h); workup The chemistry outlined above is not limited to the parent pyri- N Failed BGs: dine 6a but can also be employed on mono (6b, 6d-i) or bis (6c) substituted pyridines. Pyridines 35, 39, and 41 are new compounds RfO2C and might be challenging to access controllably from the parent O2C O2C 13g + CO2Rf pyridines in other ways. Pyridines such as 37, 38 (ca. $1620/g ), CO2Et CO2Me CO2H CO2H N BG1 BG2 BG3 BG4 BG5 and 40 have previously been synthesized either through Grignard Successful BGs: 8 addition/oxidation sequences7c or via Hong’s HAT-based MeO C 2 EtO2C 10d COR CO Me OMs method employing BG’s similar to that in Figure 1B. CO2H 2 Me N CO2Et R = OMe [BG6] BG8 BG10 (83%) It is worth noting that pyridines 8, 12, 27 and 28 have been pre- 3 R = NHR [BG7] BG9 (39%) f pared on a gram-scale with no significant reduction in yield.
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