We thank the Royal Society (ADS), Syngenta/EPSRC (DGS), and The Carnegie Trust for the Universities of Scotland (LCM) for funding, and the EPSRC National Mass Spectrometry Service Centre (Swansea). The research leading to these results has received funding from the ERC under the European Union’s 7th Framework Programme (FP7/2007-2013)/ERC grant agreement no. 279850.
Isothiourea-Mediated One-Pot Synthesis of Functionalized Pyridines†
Article first published online: 17 SEP 2013
© 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Angewandte Chemie International Edition
Volume 52, Issue 44, pages 11642–11646, October 25, 2013
How to Cite
Stark, D. G., Morrill, L. C., Yeh, P.-P., Slawin, A. M. Z., O'Riordan, T. J. C. and Smith, A. D. (2013), Isothiourea-Mediated One-Pot Synthesis of Functionalized Pyridines. Angew. Chem. Int. Ed., 52: 11642–11646. doi: 10.1002/anie.201306786
- Issue published online: 21 OCT 2013
- Article first published online: 17 SEP 2013
- Manuscript Received: 2 AUG 2013
- Funded Access
- Royal Society
- Carnegie Trust
- European Union. Grant Number: 279850
- Lewis base;
Pyridines are an extremely privileged heterocyclic class commonly found in natural products and functional materials. They are also important building blocks in both the agrochemical and pharmaceutical industries.1 Consequently, a vast array of synthetic methods has been successfully developed to access these useful molecules.2 Despite many recent advances, novel methods for the synthesis of highly functionalized pyridines in a selective and high yielding manner from accessible starting materials remains an important goal within the synthetic community.3
Following the demonstration by Romo and co-workers of generating ammonium enolates4 from carboxylic acids,5 we have shown that isothioureas6, 7 catalyze the intermolecular Michael addition/lactonization/lactamization of arylacetic acids and electron-deficient Michael acceptors.8 To expand this mode of activation, we questioned whether this methodology could be used to access functionalized pyridines. Conceptually, an isothiourea-catalyzed reaction of an acetic acid bearing an α-leaving group with a suitably electron-deficient α,β-unsaturated ketimine 19 would result in Michael addition/lactamization with subsequent elimination to form the pyridones 2 (Scheme 1).10 Subsequent N- to O-sulfonyl migration11 would allow the pyridines 3 to be accessed directly in one pot. Importantly, in this process the activating sulfonyl group on the ketimine would be transformed into a synthetically useful functional handle (the 2-sulfonate group) in the resultant pyridines, thus allowing subsequent derivatization into a variety of products.
After initial screening,12 commercially available (phenylthio)acetic acid 4 was identified as a suitable acid in this process. Treatment of 4 with pivaloyl chloride and iPr2NEt gave the corresponding mixed anhydride in situ. Subsequent addition of the α,β-unsaturated ketimine 513 in the presence of the isothiourea DHPB (6; 20 mol %) in CH2Cl2 at 0 °C for 4 hours afforded the pyridine 7 in only 7 % yield after chromatographic purification,14 despite complete consumption of 5 (Table 1, entry 1). Optimization of this process showed that a combination of increased temperature and changing the solvent gave a higher yield of the isolated pyridine (entries 2–4). The increased temperatures are necessary to promote effective N- to O-sulfonyl migration in this process, with lower temperatures leading to mixtures of the intermediate pyridone and desired pyridine. The use of a microwave reactor led to good product yields (entry 5), and alternative reaction concentrations or catalysts (8–10) had a negative effect upon the yield of the isolated product (entries 6–10). Using 6 and extending the reaction time to 16 h in THF at 80 °C was determined to be the optimal reaction conditions, thus giving 7 in 67 % yield (entry 10).15
|Entry||Cat.||Solvent||T [°C]||t [h]||Yield [%][a]|
The generality of this process was next investigated (Table 2). Under optimized reaction conditions, this process tolerates a variety of α,β-unsaturated ketimines. The N-sulfonyl group (benzenesulfonyl and tosyl) can be altered, whilst a variety of different esters (methyl, ethyl, and benzyl) are also tolerated at the β position. Additionally, a range of aryl groups bearing electron-withdrawing (-NO2, -CN,-CF3), electron-donating (-OMe, -Me), and halogen (-F, -Cl) substituents are efficient substrates in this process, along with alkyl substitution. The functionalized trisubstituted pyridines 7 and 11–21 are formed in moderate to good yields following the three consecutive synthetic transformations in one pot.
Given the wide interest in the preparation of functional heterocycles containing a trifluoromethyl unit, this protocol was extended to the synthesis of 4- and 6-trifluoromethyl-containing pyridines. Trifluoromethyl-containing α,β-unsaturated ketimines were readily prepared from the corresponding enones and used in this protocol, thus giving pyridines in acceptable yields (40–66 %; Table 3). Variation of the sulfonyl unit, as well as incorporation of heteroaryl (2-furyl and 2-thiophenyl) and aryl substituents was explored, with the incorporation of 3- and 4-bromosubstituted aromatics targeted to allow the possibility of derivatization by cross-coupling.16, 17 This pyridine-forming protocol is readily applicable to large-scale synthesis, thus forming the pyridine 22 on a 26 mmol scale using 6 (20 mol %) to generate 5.2 g of product (51 % yield). The pyridine 22 can also be accessed from the corresponding (Z)-ketimine under standard reaction conditions in 54 % yield. In addition, the isomeric pyridine 33 could be isolated in 40 % yield from the corresponding ketimine after heating for 48 h.18
The proposed reaction mechanism proceeds by initial formation of the mixed anhydride 34 from 4 and pivaloyl chloride with subsequent N-acylation of DHPB to generate the corresponding acyl isothiouronium ion 35 (Figure 1). Deprotonation generates the (Z)-enolate 36, which undergoes Michael addition with the α,β-unsaturated ketimine 37 and subsequent intramolecular lactamization to generate the corresponding dihydropyridinone 38 and regenerate DHPB. Subsequent elimination of thiophenol gives the pyridone 39, which undergoes thermally promoted N- to O-sulfonyl migration to afford the pyridine 40.19
Within the literature, sporadic examples of the key N- to O-sulfonyl rearrangement utilized in this process have been observed, usually as an undesired nonproductive pathway in thermally promoted Diels–Alder reactions of sulfonyl pyridones.11 To understand this process further, a crossover experiment was performed to determine if the N- to O-sulfonyl migration process involves an intra- or intermolecular transfer (Scheme 2). Reaction of 4 (1 equiv) with a 50:50 mixture of the ketimines 41 and 42 under the optimized reaction conditions led exclusively to the pyridines 24 and 28, respectively, in a 50:50 mixture, and is consistent with intramolecular N- to O-sulfonyl transfer from an intermediate pyridone being involved within this process.
The synthetic utility of the newly installed 2-sulfonate functional handle was next demonstrated through a series of product derivatizations to install H, aryl, heteroaryl, alkyl, and amino substituents (Scheme 3). For example, 22 can be reduced to give the 2,4-substituted pyridine 43 in 89 % yield,20 and it also readily undergoes SNAr with morpholine to give 44 in 85 % yield.21, 22 The pyridine substrates are compatible with traditional cross-coupling methodologies, thus leading to diverse 2,4,6-substituted pyridines. For example, 22 undergoes a Mizoroki–Heck reaction with N-vinylacetamide to afford the pyridine 45 in 76 % yield,23 Suzuki coupling to give 46 in 81 % yield,24, 25 and Kumada cross-coupling to give 47 in 66 % yield.26 In addition to sp2–sp2 coupling reactions, iron-catalyzed sp2–sp3 coupling of 22 with n-hexylmagnesium bromide gives 48 in 74 % yield.27, 28
Finally, the utility of this approach for the synthesis of medicinally relevant pyridine-containing molecules was illustrated. For example, the pyridine 50, which possesses activity as a COX-2 inhibitor (<0.5 mM activity, >100 fold selectivity for COX-2 versus COX-1)29 for the treatment of depressive disorders, can be made in 49 % yield over two synthetic steps from the α,β-unsaturated ketimine 49 (14 % overall yield from commercially available starting materials, Scheme 4).
In conclusion, we have developed an isothiourea-catalyzed, one-pot synthesis of 2,4,6-substituted pyridines bearing a readily derivatized 2-sulfonate functionality from (phenylthio)acetic acid and range of α,β-unsaturated ketimines. This process proceeds by intermolecular Michael addition/lactamization, thiophenyl elimination, and N- to O-sulfonyl migration, wherein the N-sulfonyl activating group within the α,β-unsaturated ketimine is transformed into a valuable 2-sulfonate functional handle in the resulting pyridine. Functionalization of this group allows the rapid assembly of both novel and biologically relevant pyridines. Current research from this laboratory is directed towards developing new applications of isothioureas in catalysis.
- 2For reviews, see:
- 2cChem. Rev. 2006, 106, 4664;, ,
- 2fSynlett 2007, 1085;, , ,
- 3For selected recent methods to access substituted pyridines, see:
- 6For a recent review detailing the use of isothioureas in nucleophilic catalysis, see:
- 7For pioneering work, see:
- 9During the preparation of this manuscript, Loh and co-workers published an alternative approach to pyridines using ketimines (1 equiv) and allenoates (2 equiv) as starting materials (Ref [3j]).
- 10For a process involving elimination of a sulfoxide to generate pyridones, see:
- 11For examples of this rearrangement, usually considered to be an undersired, nonproductive pathway, see:
- 11iSynlett 2007, 1043;, , , ,
- 11lTetrahedron 2008, 64, 5291. For a related transformation, see: Chem. Eur. J. 2007, 13, 9686. After acceptance of this manuscript a recent application of this process was disclosed: ., , , ,
- 12Initially, bromo- and chloroacetic acid were tested in this protocol although neither resulted in any conversion into the pyridine 7.
- 13All ketimines were prepared in three steps from commercially available starting materials by established literature methods. See the Supporting Information for full details.
- 14The structure of 7 was unambiguously confirmed by X-ray crystal structure analysis. CCDC 953451 (7) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
- 15All pyridine-forming reactions using commercially available (phenylthio)acetic acid (4) were carried out using bench-grade solvents under air as standard.
- 16For a general review on palladium-catalyzed cross-coupling, see: Angew. Chem. 2012, 124, 5150; Angew. Chem. Int. Ed. 2012, 51, 5062., , , ,
- 18A selection of other N-sulfonyl ketimines including α- and α,β-substituted derivatives were tested in this protocol and did not afford the desired pyridine products, but instead led to isolable dihydropyridinones or pyridones. See the Supporting Information for details.
- 19At the moment we cannot unambiguously distinguish between the N-acylation/deprotonation mechanism to generate 36 as depicted in Figure 1 and the alternative process which proceeds by ketene formation and addition of DHPB.
- 22An alternative SNAr with cyclohexylamine proceeded in 79 % yield. See the Supporting Information for full details.
- 25An alternative Suzuki coupling with 3-furanylboronic acid proceeded in 70 % yield. See the Supporting Information for full details.
- 28The 2-sulfonate group in 7 can also be hydrolyzed by treatment with nBu4NOH to afford a pyridone in 89 % yield. See the Supporting Informationfor full details.
- 29a2004;, , , , , WO 2004/024691,
- 29b2005., , , WO 2005/048999,
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