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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- 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). Herein we disclose a highly practical method featuring on a and carboxylic acid alkyl donors, is operationally simple, scalable, new blocking group based on a simple fumarate backbone (6a) en- and is applied to access known structures in a rapid and inexpensive abling classic Minisci decarboxylative alkylations to take place fashion. Finally, this work points to an interesting strategic depar- with exquisite selectivity at C–4 (Figure 1C) under acid-free con- ture for the use of Minisci chemistry at the earliest possible stage ditions. Emblematic of this advance is the preparation of 4-cyclo- (native pyridine) rather than current dogma that almost exclusively hexylpyridine (8) which cannot be accessed from pyridine in a syn- employs Minisci as a late-stage functionalization technique. thetically useful yield and as a mixture of isomers under four dif- ferent Minisci-type conditions. Tactically, scalable access to valu- able structures such as 8 (81% isolated yield from 6a) can now be enabled with a dramatic reduction in cost. From a strategic perspec- The power of C–H functionalization logic in the context of syn- tive, this work opens a new dimension of retrosynthetic logic for thesizing heteroaromatic structures is undeniable.1 Its increasing use of the Minisci transform at an early rather than late stage. 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 R X relationships to be rapidly explored. In particular, the venerable 4 unselective cross coupling Minisci reaction and its many variants have long been recognized 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] 7 CO Et 8, C4 terials have appeared over the past decade (Figure 1B) all based 6a 2 on blocking competitive C–2 sites using transient or covalently linked species at the pyridine nitrogen. Nakao’s pioneering studies Figure 1. (A) An unsolved challenge in the field of Minisci reac- using bulky Al-based Lewis-acids in an elegant hydroarylation pro- tion. (B) Literature precedent. (C) Comparison experiment with cess is limited to olefin donors and must be performed in a glove pyridine box.8 The Fier group at Merck invented clever oxime-based pyri- dinium species that could be employed in three examples of C–C Guided by colleagues at Syngenta (E.G.) several criteria needed bond formation with carbon-based nucleophiles.9 Finally, the Hong to be met for a practical blocking group (BG) design, such as: (1) derivation from feedstock materials (ca. $5/mole), (2) simple in- Numerous secondary carboxylic acids were employed to access stallation and removal, (3) high stability, ease of handling, and sol- such pyridines with high simplicity when placed in context. For ex- ubility in multiple solvents, and most critically, (4) complete regi- ample, pyridine 8 has been prepared multiple times leading either ochemical control to avoid the need for any chromatography. To- to mixtures (e.g., Figure 2B) or requiring pre-functionalized pyri- wards this end, multiple BGs were explored with most falling into dines (ca. $584/g13d).19 Similarly, pyridine 18 has been accessed one of two categories (Figure 2A): (1) simple BG installation with from 4-bromopyridine through photochemical and electrochemical either modest or low reactivity under Minisci conditions (BG1, 2, reductive couplings or by employing Hong’s BG (Figure 1B) and a 4, 6) or (2) difficulty in forming a stable BG adduct. After extensive Hantzsch ester radical precursor10b (ca. $150/g13e). Pyridine 21 has exploration, BG10 emerged as an ideal candidate satisfying all of been accessed either via cross coupling/Hydrogenation20a or C4-se- the criteria laid out above. BG9 was the only other moderately suc- lective Grignard addition using TBSOTf to generate a transient BG cessful one however it exhibited reduced reactivity towards Minisci and reoxidation20b (ca. $100/g13b). Cyclopropyl containing pyridine addition. The preparation of pyridinium 6a with BG10 could be 23 was accessed either from 4-bromo or 4-Bpin pyridine via Suzuki prepared through a simple, chromatography-free, two-step se- or Grignard addition/rearomatization (ca. $226/g13a).21 The trivial quence starting from commodity materials (pyridine and maleic cyclohexanone pyridine 25 has only been accessed in a controlled acid) followed by esterification. The structure of pyridinium 6a was fashion using multistep routes with protecting groups and FG ma- confirmed by X-ray crystallography and contained the ethyl sul- nipulations (ca. $871/g13f).22 fonate as a counter-anion. This crystalline salt represents a straight- Many of the quaternary center containing C-4 alkylated pyri- forward gateway to a variety of C–4 alkylated pyridines (vide infra) dines (derived from tertiary carboxylic acids) prepared here are and has been commercialized by Sigma-Aldrich (catalog # new (29-33) and are likely desirable starting materials for medici- ALD00619). nal chemistry programs. Of the known alkylated pyridines in this series, two were prepared as mixtures of regioisomers using radical A. A Fumarate-Derived Blocking Group For Minisci: Discovery chemistry (26 and 28)23,24 or via Minisci addition to 4-cyano- + 25 H -free Minisci (AgNO3, (NH4)2S2O8, 2 h); workup pyridine. N Failed BGs: The chemistry outlined above is not limited to the parent pyri- dine 6a but can also be employed on mono (6b, 6d-i) or bis (6c) RfO2C substituted pyridines. Pyridines 35, 39, and 41 are new compounds O2C O2C + CO2Rf and might be challenging to access controllably from the parent CO2Et CO2Me CO2H CO2H N BG1 BG2 BG3 BG4 BG5 pyridines in other ways. Pyridines such as 37, 38 (ca. $1620/g13g), Successful BGs: 8 and 40 have previously been synthesized either through Grignard MeO C 2 EtO2C 7c COR CO Me OMs addition/oxidation sequences or via Hong’s HAT-based CO2H 2 Me N CO2Et 10d R = OMe [BG6] method employing BG’s similar to that in Figure 1B. BG8 BG10 (83%) 3 R = NHR [BG7] BG9 (39%) f It is worth noting that pyridines 8, 12, 27 and 28 have been pre- B. Fumarate-Pyr (6a): An Inexpensive Gateway to C-4 Alkyl Pyridines pared on a gram-scale with no significant reduction in yield. The limitations of this reaction (see SI for full disclosure) stem from the acidic conditions used to install the BG and a lack of tolerance for N H2O, !, 2 h H2SO4 (2 eq.) $33/kg preexisting C–2 functionality. then N N + EtOH (0.2 M), OSO3Et AcOH CO2H Having facile access to pure C–4 alkylated pyridines open up a HO2C , 18 h CO2Et O2C ! (1.2 eq.) EtO2C new opportunity for early-stage Minisci chemistry to be employed 9 6a [X-ray] Aldrich Cat # !, 24 h ALD00619 in the synthesis of 2,4-difunctionalized systems.
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