Driving Recursive Dehydration by PIII/PV Catalysis: Annulation of Amines and Carboxylic Acids by Sequential C–N and C–C Bond Formation The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Lecomte, Morgan, Jeffrey M. Lipshultz, Shin-Ho Kim-Lee, Gen Li, and Alexander T. Radosevich, "Driving Recursive Dehydration by PIII/PV Catalysis: Annulation of Amines and Carboxylic Acids by Sequential C–N and C–C Bond Formation." Journal of the American Chemical Society 141, 32 (July 2019): p. 12507-12 doi 10.1021/ jacs.9b06277 ©2019 Author(s) As Published 10.1021/jacs.9b06277 Publisher American Chemical Society (ACS) Version Final published version Citable link https://hdl.handle.net/1721.1/124882 Terms of Use Creative Commons Attribution-NonCommercial-NoDerivs License Detailed Terms http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article published under a Creative Commons Non-Commercial No Derivative Works (CC-BY-NC-ND) Attribution License, which permits copying and redistribution of the article, and creation of adaptations, all for non-commercial purposes. Communication Cite This: J. Am. Chem. Soc. 2019, 141, 12507−12512 pubs.acs.org/JACS Driving Recursive Dehydration by PIII/PV Catalysis: Annulation of Amines and Carboxylic Acids by Sequential C−N and C−C Bond Formation † § † § † ‡ † Morgan Lecomte, , Jeffrey M. Lipshultz, , Shin-Ho Kim-Lee, , Gen Li, † and Alexander T. Radosevich*, † Department of Chemistry, Massachusetts Institute of Technology, 02139 Cambridge, Massachusetts, United States ‡ Departamento de Química Organica,́ Facultad de Ciencias, Universidad Autonomá de Madrid, Cantoblanco, 28049 Madrid, Spain *S Supporting Information ABSTRACT: A method for the annulation of amines and carboxylic acids to form pharmaceutically relevant azaheterocycles via organophosphorus PIII/PV redox catalysis is reported. The method employs a phosphetane catalyst together with a mild bromenium oxidant and terminal hydrosilane reductant to drive successive C−N and C−C bond-forming dehydration events via the serial action of a catalytic bromophosphonium intermediate. These results demonstrate the capacity of PIII/PV redox catalysis to enable iterative redox-neutral transformations in complement to the common reductive driving force of the PIII/PV couple. rogress over the past decade has established the viability − P of the PIII/PVO redox couple for catalysis.1 3 In contrast to prior notions about the kinetic inertness of the PO bond, the incorporation of P into a ring structure can lead to swift deoxygenation by mild reagents such as hydrosilanes.4,5 By virtue of the reducing potential of the PIII/PV couple, many of these transformations are reductive in 6−8 Figure 1. (A) Complementary reductive and redox-neutral modes of nature (Figure 1A, left). In this vein, we have shown that III V four-membered ring organophosphorus catalysts effect reduc- P /P catalysis. (B) Catalytic heterocyclization of nitrobiaryl by 9 10 recursive deoxygenation. (C) Catalytic annulation of amines and tive conversion of nitro and sulfonyl substrates (cf. Figure carboxylic acids by recursive dehydration. 1B) in which the ability to recursively renew a reactive PIII species under conditions of PIII/PV catalysis enables a single See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. catalyst to perform successive deoxygenative operations on a dehydration reactions,”18,19 the potential to achieve recursive 11 Downloaded via MASSACHUSETTS INST OF TECHNOLOGY on November 25, 2019 at 19:45:24 (UTC). substrate (i.e., autotandem catalysis ). dehydrations in an autotandem catalytic manner via a net In addition to reductive chemistry, the versatile PIII/PV redox-neutral mode of PIII/PV catalysis could be expected to driving force can be adapted to achieve net redox-neutral present new opportunities for serial bond formation. transformations when paired with an appropriate oxidant as We show here an annulation of amines and carboxylic acids evoked in Mukaiyama’s conceptualization of an “oxidation- via recursive dehydration driven by a redox-active organo- reduction condensation.”12 Within a PIII/PV-catalytic context,13 phosphorus catalyst cycling in the PIII/PV couple (Figure 1C). the introduction of a mild chemoselective halenium oxidant, This autotandem catalytic system enables the elaboration of for instance, can shunt the reductive manifold into a net redox- simple starting materials into pharmaceutically relevant neutral mode, where the key reactive catalytic intermediate is azaheterocycles through a condensation/cyclodehydration not a phosphine but rather a halophosphonium cation14,15 sequence in a one-pot catalytic protocol. The success of the (Figure 1A, right). Indeed, halophosphonium intermediates approach relies on the mutual compatibility and functional have been invoked by Rutjes and van Delft5 and Mecinovic16́ interplay of the reducing and oxidizing reagents with the in the context of PIII/PV-catalyzed Appel halogenation and N- organophosphorus catalyst to orchestrate a sequence of acylation reactions, respectively.17 In view of the fact that phosphonium reagents have been described as having “virtually Received: June 12, 2019 ideal properties as selective oxygen extractors for net Published: July 25, 2019 © 2019 American Chemical Society 12507 DOI: 10.1021/jacs.9b06277 J. Am. Chem. Soc. 2019, 141, 12507−12512 Journal of the American Chemical Society Communication distinct C−N and C−C bond-forming events. The ability of With respect to catalyst, variation of the phosphetane PIII/PV redox catalysis to encompass such recursive dehy- exocyclic moiety to ethyl (5·[O], entry 6), phenyl (6·[O], dration stands as a complement to existing deoxygenation entry 7), or pyrrolidino (7·[O], entry 8) all resulted in methods, thus broadening the scope of transformations substantial decrease in the efficiency of the reaction, while accessible to this catalytic mode. acylic phosphine oxides (8·[O] or 9·[O], entry 9) fail to To evaluate the possibility of recursive dehydration driven promote the cyclocondensation (see Supporting Information). by PIII/PV redox cycling, the tandem amidation/cyclodehydra- Control experiments confirm that no azaheterocycle product is tion of amine 1a and carboxylic acid 2a to generate observed in the absence of any of 4·[O], phenylsilane, or pyrroloquinoxaline 3a was evaluated (Table 1). Optimal DEBM (entries 10−12).22 Furthermore, employing PIII species 4 or pregenerated bromophosphonium [4·Br]Br23 in place of Table 1. Discovery and Optimization of Phosphacatalytic phosphine oxide 4·[O] resulted in comparable efficiency, Iterative Condensation/Annulation of Amine and consistent with the notion of PIII/PVO redox cycling (entries Carboxylic Acid 13 and 14). The optimized phosphacatalytic protocol provides direct access to complex azaheterocycles from simple and readily available amine and carboxylic acid starting materials (Figure 2). A variety of carboxylic acids are efficiently incorporated into pyrroloquinoxalines, including those possessing olefinic and aryl functionalities (3c−3i,54−89% yields). This protocol was also readily translated to larger-scale reactions, as a 5 mmol scale reaction of 1-(2-aminophenyl)pyrrole and butyric acid provided 1.04 g of compound 3b in 99% yield with 8 mol % loading of organophosphorus catalyst 4·[O]. As demonstrated by products 3d−3i,thereactionefficiency is relatively entry R POX+ source yielda (%) independent of substitution on benzoic acid coupling partners, 3 fi − 1 4·[O] DEBM 94 (84)b including changing steric pro le (54 89% yields). Critically, · acids containing polar functionalities, including alkyl ethers, 2 4 [O] DEMBM 90 ffi 3 4·[O] NBS 10 thioethers, sulfonamides, and alkyl halides, undergo e cient 4 4·[O] DECM 0 iterative dehydration to provide heterocycles in good to · excellent yields (3a, 3j−3p,41−90% yields). Of particular note 5 4 [O] CCl4 0 6 5·[O] DEBM 26 are the amino acid-incorporating products 3k and 3p, which 7 6·[O] DEBM 46 originate from protected Ts-Gly-OH and Ts-Phe-OH. Further, 8 7·[O] DEBM 50 both primary and secondary haloalkane functionalities are III V 9 8·[O] or 9·[O] DEBM 0 conserved under this P /P -catalytic manifold (3l and 3m, 10 none DEBM 0 93% and 98% yields, respectively). Substitution on the aniline 11 4·[O] none 0 ring was well-tolerated; both ortho- and meta-substituted 12 4·[O], no PhSiH DEBM 0 pyrroloanilines were readily incorporated into heterocyclic 3 ff 13 4 DEBM 90 sca olds (3n and 3o, 86% and 95% yields, respectively). Chiral 14 [4·Br]Br DEBM 87 carboxylic acids, such as ibuprofen and naproxen, are fi aYields determined through 1H NMR analysis with the aid of an incorporated with good yield and high stereochemical delity (3q, 67%, 95:5 enantiomeric ratio (e.r.); 3r, 68%, 92.5:7.5 e.r.) internal standard. See Supporting Information for full synthetic details fi and yields of intermediate amide 3a′. bIsolated yield on 0.4 mmol under modi ed recursive dehydration conditions (precatalyst scale. DCE = 1,2-dichloroethane; DEBM = diethyl bromomalonate; [4·Br]Br, MeCN, 50 °C; see Supporting Information for full DEMBM = diethyl (methyl)bromomalonate; NBS = N-bromosucci- synthetic details). nimide; DECM = diethyl chloromalonate. When N-alkyl amine substrates were initially employed under standard conditions, an undesired byproduct arising from N-alkylation by DEBM was identified by gas chromatog- conditions using 1,2,2,3,4,4-hexamethylphosphetane