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Protokoll Handledarmöte 2020-02-14 http://www.diva-portal.org Postprint This is the accepted version of a paper published in Organic Letters. This paper has been peer-reviewed but does not include the final publisher proof-corrections or journal pagination. Citation for the original published paper (version of record): Colas, K., dos Santos, A C., Mendoza, A. (2019) i-Pr2-NMgCl·LiCl Enables the Synthesis of Ketones by Direct Addition of Grignard Reagents to Carboxylate Anions Organic Letters, 21(19): 7908-7913 https://doi.org/10.1021/acs.orglett.9b02899 Access to the published version may require subscription. N.B. When citing this work, cite the original published paper. Permanent link to this version: http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-175818 i-Pr2NMgCl·LiCl Enables the Synthesis of Ketones by Direct Addi- tion of Grignard Reagents to Carboxylate Anions Kilian Colas, A. Catarina V. D. dos Santos and Abraham Mendoza* Department of Organic Chemistry, Stockholm University, Arrhenius Laboratory, 106 91 Stockholm (Sweden) Supporting Information Placeholder direct Grignard - carboxylate coupling 1 R MgX + i-Pr2NMgCl•LiCl 1 MgX ( ) R * CO2 i-Pr i-Pr L L O [Mg] N O ideal ( ) * Mg Li (*) sources 1 1 2 R O Cl R R R2 L O ketone [proposed structure] products base R1 OH [in-situ from commercial] ◾ >30 examples ◾ scalable ◾ facile isotopic-labelling ABSTRACT: The direct preparation of ketones from carboxylate anions is greatly limited by the required use of organolithium reagents or activated acyl sources that need to be independently prepared. Herein, a specific magnesium amide additive is used to activate and control the addition of more tolerant Grignard reagents to carboxylate anions. This strategy enables the modular synthesis of ketones from CO2 and the preparation of isotopically-labelled pharmaceutical building blocks in a single operation. Ketones (1) are one of the cornerstones of organic chemistry, The addition of aromatic Grignard reagents to benzoates being a fundamental class of products and essential synthetic would give rise to important benzophenone compounds,1h but it intermediates. Aromatic ketones are particularly relevant drugs is particularly problematic due to the lower reactivity of aro- and fragrances, and they are key to the synthesis of heterocyclic matic carboxylates and aryl Grignard reagents. To the best of cores in valuable products.1 As a result, extensive research has our knowledge, this reaction has only been studied using che- been dedicated to obtain ketones from raw carboxylic acids (2) late-assisted heteroaryl substrates,17 or lithium propylamide as 18 and CO2 (3). However, the addition of localized carbon nucleo- additive (Scheme 1B). However the application of these pro- philes to carboxylic acids is a key transformation that remains cesses in organic synthesis is severely limited by the narrow challenging after decades of research (Scheme 1A). Most ap- scope, and the inhibition in the presence of tetrahydrofuran,18 proaches elaborate carboxylic acids 2 into more electrophilic which is the most common solvent to synthesize, store and dis- derivatives 4, such as acyl chlorides,2 anhydrides,3 thioesters,2f,4 tribute Grignard reagents.16,19 Overcoming the challenges asso- cyanides,5 ketimines,6 imides,7 amides8 and Weinreb amides.9 ciated with the direct addition of Grignard nucleophiles (8) to Special carbon nucleophiles 5 with lower reactivity like cu- carboxylate anions (6) is key to enable an extended modular 10 4,11 2g,3b,7,12 13d prates, organozincs, and boronates, are often used to synthesis of ketones from CO2 (3). Carboxylates 6 are readily 20 avoid the rapid over-addition to the resulting ketone products 1. obtained from aryl Grignard reagents (8) and CO2 (3), and Alternatively, the direct coupling of carbon nucleophiles with these anions could ideally undergo coupling with a second or- unactivated carboxylic acids requires unstable organolithium ganomagnesium nucleophile. The enhanced scope bestowed by reagents, often in excess.13,14 These addition reactions to lithium Grignard reagents16 would enable access to diversely function- 13d carboxylate anions Li-6 benefit from the stability of the addi- alized ketones in a single operation. The use of CO2 also of- tion complex Li-7, but are limited by competing metalation re- fers a more sustainable alternative for scale-up than current actions, carbonyl reduction, and the narrow functional scope of methods based on CO, CO-sources and/or expensive transition- the lithium organometallics.14 Grignard reagents (8) are pre- metal catalysts,12,21 particularly for the synthesis of isotopically ferred nucleophiles for their enhanced stability and functional- carbon-labelled pharmaceuticals used in bio-distribution stud- group tolerance, particularly in large-scale processes.15,16 Un- ies and trace analysis.22 like organolithiums, Grignard reagents (8) are poorly reactive We have recently discovered the differential behavior of Gri- towards carboxylate anions (6), and the resulting addition inter- gnard reagents in combination with the hindered turbo-Hauser mediates are unstable, giving rise to tertiary alcohol over-addi- 23 base i-Pr2NMgCl·LiCl (9a) in the context of Pummerer reac- 13d,14 tion by-products. tions.24 We hypothesized that the enhanced “ate” character19a,25 of the turbo-organomagnesium amides thus formed, could (1) efficiency of the reaction (entry 7). LiCl is essential in the enhance the nucleophilicity of the initial Grignard reagent to Hauser base to achieve high conversion (entry 8), probably in- overcome the low electrophilicity of the carboxylate anion, (2) dicating its role in the aggregation27 of the turbo-organomagne- stabilize the addition complex through strong coordination2e,9a sium amide formed upon mixing of the Grignard 8a and 9a (for and/or rapid intramolecular enolization, and in a broader sense discussion, see Scheme 4).28 Control experiments in the absence (3) address the efficiency and selectivity problems that are as- of i-Pr2NMgCl·LiCl (9a; entry 9) confirm its critical role at pro- – sociated with classic organometallic "ate" reagents [R3M] moting the addition reaction to the magnesium carboxylate. (M=Mg, Cu, Zn).10,11,25 Furthermore, related lithium amides 9e,f or LiCl alone were Scheme 1. State-of-the-art in the synthesis of ketones and our deemed ineffective (entries 10-12), thus indicating the singular approach using Grignard reagents. activating effect of the magnesium amide LiCl complex 9a in the addition to the carboxylate anion. To the best of our A synthesis of ketones from carboxylic acids and CO2 knowledge, organomagnesium amides have only been used as 28c [high electrophilicity] [low nucleophilicity] bases in challenging deprotonation reactions, and the perfor- O mance of their LiCl-adducts as carbon nucleophiles has not multi-step route 2 24 large scope R M’ been explored before our work. R1 X X= Cl, Weinreb, M’= Cu, Zn, Table 1. Activation and control of Grignard reagents by BF K, MgR SR, O2CR,.. 3 i-Pr NMgCl·LiCl (9a). 4 - activated 5 - custom 2 carbonyl derivative carbon-nucleophile O O Ph–MgBr (8a; 1.2 equiv) base additive (9; 1.2 equiv) O OH OH O M or CO + + R1 OH 2 R1 R2 ArCO2H toluene : THF Ph Ph Ar O Ar Ph Ar Ar 2 3 1 r.t. Ph H abundant feedstocks ketones 2a M-6a - Ar=3-tol 1a 10a 11a recovered composition (%)a ## MM additiveadditive (9) (9) 2a (%)a 1a (%)a 10a (%)a 11a (%)a Li Li 2 O Li 2 2a 1a 10a 11a 1-step route R Li R Li H2O 1 Na — 94 0 0 0 O O narrow scope 18 –R2H R1 O 12 NaNa PrNHLi– (9b) 97 940 0 0 0 0 0 R1 R2 3 Na i-Pr2NMgCl•LiCl (9a) 9 77 14 0 Li-6 Li-7 2 Na PrNHLi 97 0 0 0 4 MgCl i-Pr2NMgCl•LiCl (9a) 0 92 0 5 carboxylate anion Li or special substrates i b 35 MgClNa i-PrPrNMgCl•LiCl2NMgCl (·9aLiCl) (9a67) 928 77 0 14 5 0 [low electrophilicity] required for stability 2 c 6 MgCl i-Pri 2NMgCl•LiCl (9a) 26 49 3 25 4 MgCl Pr2NMgCl·LiCl (9a) 0 92 0 5 7 MgCl TMPMgCl•LiCl (9c) 72 26 0 0 B addition of Grignard nucleophiles to carboxylate anions i b 58 MgClMgCl i-PrPr2NMgCl2NMgCl (9d) ·LiCl (9a55) 6736 28 4 0 4 5 [R2 Mg]– organometallic “ate” n 9 MgCl —i 64 c 18 15 0 or w/ RNHLi additive18 6 MgCl Pr2NMgCl·LiCl (9a) 26 49 3 25 10 MgCl i-Pr2NLi (9e) 70 22 4 8 ◾ low reactivity ◾ chelation needed 117 MgClMgCl TMPLiTMPMgCl (9f) ·LiCl (9c61) 7225 26 3 0 8 0 ◾ unstable intermediate ◾ limited scope 12 MgCl PrNHLii (9b) 65 21 14 0 8 MgCl Pr2NMgCl (9d) 55 36 4 4 O M O 13 MgCl LiCl (9g) 57 15 28 0 + R2 MgX 9 MgCl – 64 18 15 0 R1 O 1 2 R R i 6 8 1 10 MgCl Pr2NLi (9e) 70 22 4 8 carboxylate Grignard anion nucleophile ketones 11 MgCl TMPLi (9f) 61 25 3 8 i-Pr2NMgCl•LiCl(9a) 12 MgCl PrNHLi (9b) 65 21 14 0 [ this work ] ◾ high reactivity ◾ no chelation 13 MgCl LiCl (9g) 57 15 28 0 ◾ stable intermediate ◾ scalable In agreement with the general notion in the litera- ture,10,13a,13d,17-18,26 our exploratory studies (Table 1) revealed Conditions: 2a (0.1 mmol), NaH or t-BuMgCl (0.1 mmol), tolu- that no addition of phenylmagnesium bromide (8a) occurs to ene, 0 °C; PhMgBr (8a, 0.12 mmol) and 9 (0.12 mmol), 0 °C, ul- trasound; r.t., 7 h. aDetermined by 1H-NMR using 1,1,2,2-tetrachlo- the sodium carboxylate (Na-6a; entry 1), and a similar result is b c obtained in the presence of PrNHLi (9b; entry 2), probably due roethane as internal standard.
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