Letter Cite This: Org. Lett. 2017, 19, 6720−6723
pubs.acs.org/OrgLett
Synthesis of 2‑Pyridinemethyl Ester Derivatives from Aldehydes and 2‑Alkylheterocycle N‑Oxides via Copper-Catalyzed Tandem Oxidative Coupling−Rearrangement Chang-Sheng Wang, Thierry Roisnel, Pierre H. Dixneuf, and Jean-François Soulé* Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes “Organométalliques: Matériaux et Catalyse”, Campus de Beaulieu, 35042 Rennes, France S Supporting Information *
ABSTRACT: Successful benzylic C(sp3)−H acyloxylation of 2-alkylpyridine, 2-alkylpyrazine, and 2-alkylthiazole compounds was achieved using simple aldehydes. This was carried out via a copper-catalyzed tandem reaction, involving oxidative esterification followed by O-atom transfer of the resultant high yield formed Boekelheide intermediate. The method enables the preparation of functional heterocycles and the desymmetrization of 2,6-dialkylpyridines for efficient synthesis of dissymmetric pincer ligands, thus offering a new life for more practical Boekelheide rearrangement.
P
yridines play an important role in synthetic chemistry as one of the most dominant heteroarenes in pharmaceuticals and natural products.1 In particular, they are useful in molecular materials,2 and as ligands in organometallic chemistry,3 including high-potential photocatalysis.4 One of the most common synthetic approaches to pyridine-containing targets rely on cycloaddition or condensation reactions using expensive noble metals.5 The recent development of crucial pincer ligands based on functional pyridines for creative pincer-metal catalyzed reaction requires the discovery of more simple and particle access to multifunctionalized pyridines.6 Among synthetic intermediates of pyridine ligands, 2-pyridinemethyl esters are important and they are generally obtained via multistep synthesis including oxidation−reduction sequences.7 In 1954, Boekelheide reported an efficient pathway to obtain pyridin-2-ylmethanol derivatives from acyl chloride and 2-methylpyridine N-oxide via the rearrangement of the 1-acetoxypyridin-1-ium intermediate (Figure 1a).8 However, the Boekelheide reaction is of limited utility as (i) it gives a mixture of sp3/sp2-oxylation products, including chlorinated product and (ii) it shows poor substrate scope.8 Alternative strategies for the higher yield synthesis of the 2-pyridinemethyl esters involve the use of activating reagents such as anhydrides,9 although such protocols suffer from poor atom efficiency. Recently, cross-dehydrogenative couplings (CDC) have been introduced as an eco-friendly substitute protocol allowing aldehydes to be employed as more convenient acyl sources.10 Indeed, aldehydes are cheap, abundant, water tolerant, easy to handle, and noncorrosive starting materials, making them ideal candidates for industrial applications compared to anhydrides and acyl chlorides. Since the pioneer work by C.-J. Li on oxidative amidation and esterification from aldehydes catalyzed by copper in the presence of peroxide (Figure 1b),11 such CDC couplings have been widely applied in oxidative amides,12 esters,13 or ketones synthesis.14 Interestingly, Barbas and co-workers © 2017 American Chemical Society
Figure 1. Cross-dehydrogenative couplings.
reported the metal-free CDC from aldehydes with N-hydroxyphthalimide for the preparation of active esters (Figure 1c).15 However, there is no example of CDC reaction from aldehydes with 2-alkylpyridine N-oxides, although it could allow the one-pot synthesis of 2-pyridinemethyl esters. However, such CDC with heterocycles is very challenging because there are many possible side-reaction pathways including C(sp2)-acylation.16 Under CDC conditions, Wu et al. has reported that 2-methylquinoline N-oxide can be acetoxylated without O-atom transfer.17 However, Received: November 6, 2017 Published: December 1, 2017 6720
DOI: 10.1021/acs.orglett.7b03446 Org. Lett. 2017, 19, 6720−6723
Letter
Organic Letters no reaction occurred with 2-alkylpyridine N-oxides. Here, we report the first selective C(sp3)−H bond acyloxylation of 2alkylpyridine and derivatives via a copper-catalyzed tandem oxidative process starting from 2-alkylheterocycle N-oxides and simple aldehydes (Scheme 1d). Initial optimization was performed using 2-methylpyridine Noxide and benzaldehyde with DTBP (di-tert-butyl peroxide) as the oxidant in tBuOH/DCE at 120 °C (Table 1); such conditions
ligands (L1−L4), and the best yield of 83% was obtained using 1,10-phenanthroline (L3) (Table 1, entries 6−9). Other oxidants such as TBHP (tert-butyl hydroperoxide) and CHP (cumene hydroperoxide) were less effective, while PhI(OAc)2 was completely inactive (Table 1, entries 10−12). The scope of the reaction proved to be broad, with a wide range of aryl- and heteroaryl-functionalized aldehydes being suitable for this copper-catalyzed tandem oxidative reaction, affording the corresponding pyridin-2-ylmethyl benzoate in good to excellent yields (Scheme 1). For instance, benzaldehyde substituted at the para position by an electron-donating group (e.g., methyl, npentyl, and phenyl) underwent a smooth reaction to give the products 2−4 in good yields, with X-ray diffraction analysis of 4 confirming the structure (CCDC 1564793). Interestingly, aldehydes bearing an halogen atom (e.g., Cl, Br, and F) at the para or meta position are well tolerated, as the desired pyridin-2ylmethyl substituted benzoates 5−7 were obtained in 62−78% yields without the cleavage of C−X bonds, allowing further transformations. 3,4,5-Trimethoxybenzaldehyde displayed good reactivity, as 8 was isolated in 71% yield. The reaction seems to be slightly sensitive to the steric factor, as congested 2-tolualdehyde allowed the formation of pyridin-2-ylmethyl 2-methylbenzoate (9) in only 63% yield. Heteroaryl benzaldehydes including 5thienyl, 2-pyrolyl, and ferrocenecarboxaldehyde were also evaluated, and the corresponding products 10−12 were obtained with high efficiency. However, when aliphatic aldehydes are used no reaction occurred. From DMF as a cheap aldehyde source, the dimethylcarbamate 13 was obtained in only 33% yield. We next set out to evaluate the reaction scope with respect to the 2-alkylpyridine N-oxide derivatives in reactions with benzaldehyde (Scheme 2). Interestingly, this method provided
Table 1. Optimization of the Reaction Conditions
entry
cat. (x)
L
oxidant
yield in 1 (%)
1 2 3 4 5 6 7 8 9 10 11 12
− FeCl3 [RuCl2(p-cymene)]2 Co(acac)2 CuBr(Me2S) CuBr(Me2S) CuBr(Me2S) CuBr(Me2S) CuBr(Me2S) CuBr(Me2S) CuBr(Me2S) CuBr(Me2S)
− − − − − L1 L2 L3 L4 L3 L3 L3
DTBP DTBP DTBP DTBP DTBP DTBP DTBP DTBP DTBP TBHP CHP PhI(OAc)2
0 38 0 0 58 70 75 83 76 37 25 0
a L1 = 2,2′-bipyridine; L2 = 4,4′-di-tert-butyl-2,2′-bipyridine; L3 = 1,10-phenanthroline; L4 = 4,7-dimethyl-1,10-phenanthroline.
Scheme 1. Scope of (Hetero)(Aryl)Aldehydes in Cu-Catalyzed C(sp3)−H Bond Benzoxylation of 2-Methylpyridine N-Oxide
Scheme 2. Scope of 2-Alkyl Heterocycle N-Oxides in CuCatalyzed C(sp3)−H Bond Benzoxylation with Benzaldehyde
are known to generate acyl radical.16a−d No reaction occurred without catalysts (Table 1, entry 1). FeCl3 proved to be effective to catalyze tandem acylation−Boekelheide rearrangement allowing the formation of pyridin-2-ylmethyl benzoate (1) in 38% yield (Table 1, entry 2). No reaction occurred using [RuCl2(p-cymene)]2 or Co(acac)2, whereas using CuBr(Me2S), the desired product 1 was obtained in 58% yield (Table 1, entries 3−5). The yield in 1 was improved employing N,N-bidentate
the desymmetrization of one methyl group of 2,6-lutidine and 2,4,6-collidine N-oxides with the formation of monobenzoxylated products 14 and 15 in 82% and 76% yield, respectively. The optimized reaction conditions tolerated a bromo or an ester substituent on the 2-methylpyridine N-oxide partner, as 16 and 17 were isolated in good yield. Formation of tertiary carbons has been demonstrated with the synthesis of 2-ethylpyridine N-oxide 18 in 62% yield. 2-Methylquinoline N-oxide reacted via O atom transfer to deliver 19 in 68% yield. 2-Methyl-pyrazine smoothly reacted to give the pyrazin-2-ylmethyl benzoate 20 in 35% yield. Interestingly, the reaction is not limited to 6-membered 6721
DOI: 10.1021/acs.orglett.7b03446 Org. Lett. 2017, 19, 6720−6723
Letter
Organic Letters heterocycles. For instance, 2-alkylthiazole N-oxides were successfully benzoxylated to give 21 and 22 in good yields. To gain insight into the reaction mechanism, several control experiments were conducted (Scheme 3). First, from 2-
Scheme 4. Proposed Mechanism
Scheme 3. Mechanistic Investigations
should allow the formation of the Cu(III) intermediate E, which undergoes a reductive elimination to release the desired Boekelheide intermediate F and the active copper(I) A species. Then, this unstable intermediate undergoes a [3,3]-sigmatropic shift to deliver the desired sp3-benzoxylated pyridine derivatives. Finally, a gram scale reaction of 2,6-lutidine N-oxide with benzaldehyde was tested; delightfully, this reaction could be performed on 10 mmol scale and proceeded smoothly to give product 14 in 83% yield (1.9 g; Scheme 5).
methylpyridine or 3-methylpyridine N-oxide, no benzoxylated product was generated (Scheme 3a). No reaction occurred using benzoic acid or tert-butyl benzoperoxoate instead of benzaldehyde (Scheme 3a). These results strongly suggested that acyloxylation of the benzylic C(sp3)−H bond results from an O-atom transfer of the N-oxide (internal oxidant) and not from an external oxidant.18 We then carried out a TEMPO radical quenching experiment; the reaction was stopped, and only the benzaldehyde−TEMPO adduct was observed, as opposed to the 2-methylpyridine N-oxide−TEMPO adduct. This result indicates that only the acyl generation step involves a radical process, not the O-atom transfer. From 2-(methyl-d3)pyridine N-oxide19 a KIE value of 2.1 was determined from both parallel and intermolecular completion reactions,20 suggesting that the C− H bond cleavage occurred during the rate-determining step (RDS) (Scheme 3b).21 In addition, we conducted two competitive reactions to probe the substituent preference for such couplings. From an equimolar ratio of 4-chlorobenzaldehyde and 3,4,5-trimethoxybenzaldehyde (3 equiv) in the presence of 2-methylpyridine N-oxide (1 equiv), we observed the formation of a mixture of 5 and 8 in a 34:66 ratio (Scheme 3c). Electron-donation groups on the pyridine oxide favor the reaction, as after 2 h the reaction of an equimolar ratio of 2,4,6collidine oxide and 3-(ethoxycarbonyl)-2-methylpyridine Noxide in the presence of benzaldehyde give 15 and 17 in an 80:20 ratio (Scheme 3d). On the basis of the above experimental results and literature on CDC,22 a plausible mechanism is illustrated in Scheme 4. First, homolytic cleavage of the DTBP peroxide allowed the formation of the tert-butoxyl radical (tBuO•) which is trapped by the copper(I) A to generate the copper(II) alkoxide B. σ-Bond metathesis of B with a 2-alkylpyridine N-oxide regenerates intermediate C and tert-butoxide.23 Deprotonation of the benzylic position of C generates the intermediate D in an RDS. The coordination of the O-heterocycle to the copper center renders the O-atom particularly reactive toward reaction with Cbased radicals (R•), which are generated by abstraction of a hydrogen atom from benzaldehyde by a tert-butoxyl radical (tBuO•). Reaction of the acyl radical (RCO•) with Cu(II) D
Scheme 5. Application to the Synthesis of Pincer Ligand Intermediates
Interestingly, we demonstrated the synthetic utility of our novel method for the synthesis of PNN Milstein-type pincer ligands,24 through the synthesis of the intermediate 23 in 84% overall yield. The previous method, namely radical bromination of 2,6-lutidine, required a more toxic media (NBS in CCl4) and gives 23 in poor 25−40% yield.25 From 2-((Boc)amino)-6-methylpyridine Noxide, an sp3-benzoxylation reaction allowed the formation of 24 in 61% yield. Notably, the Boc group did not survive the reaction conditions and the amino group was alkylated with a radical generating from DTBP. Treatment with acid gave the aminoalcohol 25, which might be further to the pincer ligands (PNNP).26 This compound 25 was previously obtained in three steps from tert-butyl (6-methylpyridin-2-yl)carbamate in moderate overall yield for the synthesis of multidentate ligands or pharmaceuticals.27 In summary, a convenient and functional-group tolerant copper-catalyzed sp3-benxozylation of 2-alkylpyridine N-oxide 6722
DOI: 10.1021/acs.orglett.7b03446 Org. Lett. 2017, 19, 6720−6723
Letter
Organic Letters
(8) (a) Boekelheide, V.; Linn, W. J. J. Am. Chem. Soc. 1954, 76, 1286. (b) Boekelheide, V.; Lehn, W. L. J. Org. Chem. 1961, 26, 428. (c) Vozza, J. F. J. Org. Chem. 1962, 27, 3856. (d) Fontenas, C.; Bejan, E.; Haddou, H. A.; Balavoine, G. G. A. Synth. Commun. 1995, 25, 629. (9) (a) Abbate, S.; Bazzini, C.; Caronna, T.; Fontana, F.; Gambarotti, C.; Gangemi, F.; Longhi, G.; Mele, A.; Sora, I. N.; Panzeri, W. Tetrahedron 2006, 62, 139. (b) Eidamshaus, C.; Reissig, H.-U. Eur. J. Org. Chem. 2011, 2011, 6056. (c) Kawasuji, T.; Johns, B. A.; Yoshida, H.; Weatherhead, J. G.; Akiyama, T.; Taishi, T.; Taoda, Y.; Mikamiyama-Iwata, M.; Murai, H.; Kiyama, R.; Fuji, M.; Tanimoto, N.; Yoshinaga, T.; Seki, T.; Kobayashi, M.; Sato, A.; Garvey, E. P.; Fujiwara, T. J. Med. Chem. 2013, 56, 1124. (10) (a) Taylor, R. J. K.; Reid, M.; Foot, J.; Raw, S. A. Acc. Chem. Res. 2005, 38, 851. (b) Scheuermann, C. J. Chem. - Asian J. 2010, 5, 436. (c) Jeena, V.; Robinson, R. S. RSC Adv. 2014, 4, 40720. (11) (a) Yoo, W.-J.; Li, C.-J. J. Am. Chem. Soc. 2006, 128, 13064. (b) Yoo, W.-J.; Li, C.-J. Tetrahedron Lett. 2007, 48, 1033. (12) (a) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317, 790. (b) Chang, J. W. W.; Chan, P. W. H. Angew. Chem., Int. Ed. 2008, 47, 1138. (c) Ghosh, S. C.; Ngiam, J. S. Y.; Chai, C. L. L.; Seayad, A. M.; Dang, T. T.; Chen, A. Adv. Synth. Catal. 2012, 354, 1407. (d) Miyamura, H.; Min, H.; Soulé, J.-F.; Kobayashi, S. Angew. Chem., Int. Ed. 2015, 54, 7564. (13) (a) Yoo, W.-J.; Li, C.-J. J. Org. Chem. 2006, 71, 6266. (b) Gowrisankar, S.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2011, 50, 5139. (c) Liu, C.; Wang, J.; Meng, L.; Deng, Y.; Li, Y.; Lei, A. Angew. Chem., Int. Ed. 2011, 50, 5144. (d) Rout, S. K.; Guin, S.; Ghara, K. K.; Banerjee, A.; Patel, B. K. Org. Lett. 2012, 14, 3982. (14) (a) Baslé, O.; Bidange, J.; Shuai, Q.; Li, C.-J. Adv. Synth. Catal. 2010, 352, 1145. (b) Shuai, Q.; Yang, L.; Guo, X.; Baslé, O.; Li, C.-J. J. Am. Chem. Soc. 2010, 132, 12212. (15) Tan, B.; Toda, N.; Barbas, C. F. Angew. Chem., Int. Ed. 2012, 51, 12538. (16) (a) Deng, G.; Ueda, K.; Yanagisawa, S.; Itami, K.; Li, C.-J. Chem. Eur. J. 2009, 15, 333. (b) Sun, M.; Hou, L.-K.; Chen, X.-X.; Yang, X.-J.; Sun, W.; Zang, Y.-S. Adv. Synth. Catal. 2014, 356, 3789. (c) Chen, J.; Wan, M.; Hua, J.; Sun, Y.; Lv, Z.; Li, W.; Liu, L. Org. Biomol. Chem. 2015, 13, 11561. (d) Wang, Y.; Zhang, L. Synthesis 2015, 47, 289. (e) Matcha, K.; Antonchick, A. P. Angew. Chem. 2013, 125, 2136. (17) (a) Chen, X.; Zhu, C.; Cui, X.; Wu, Y. Chem. Commun. 2013, 49, 6900. (b) Huang, J.; Li, L.-T.; Li, H.-Y.; Husan, E.; Wang, P.; Wang, B. Chem. Commun. 2012, 48, 10204. (18) (a) Xiao, J.; Li, X. Angew. Chem., Int. Ed. 2011, 50, 7226. (b) Zhang, X.; Qi, Z.; Li, X. Angew. Chem., Int. Ed. 2014, 53, 10794. (c) Sharma, U.; Park, Y.; Chang, S. J. Org. Chem. 2014, 79, 9899. (d) Barsu, N.; Sen, M.; Premkumar, J. R.; Sundararaju, B. Chem. Commun. 2016, 52, 1338. (19) Pavlik, J. W.; Vongnakorn, T.; Tantayanon, S. J. Heterocycl. Chem. 2009, 46, 213. (20) See Supporting Information for more details. (21) Simmons, E. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51, 3066. (22) (a) Tran, B. L.; Li, B.; Driess, M.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 2555. (b) Zeng, H.-T.; Huang, J.-M. Org. Lett. 2015, 17, 4276. (c) Wang, C.-S.; Wu, X.-F.; Dixneuf, P. H.; Soulé, J.-F. ChemSusChem 2017, 10, 3075. (23) Jotham, R. W.; Kettle, S. F. A.; Marks, J. A. J. Chem. Soc., Dalton Trans. 1972, 1133. (24) Zhang, J.; Leitus, G.; Ben-David, Y.; Milstein, D. J. Am. Chem. Soc. 2005, 127, 10840. (25) (a) Gultneh, Y.; Yisgedu, T. B.; Tesema, Y. T.; Butcher, R. J. Inorg. Chem. 2003, 42, 1857. (b) Rojas, D.; Garcia, A. M.; Vega, A.; Moreno, Y.; Venegas-Yazigi, D.; Garland, M. T.; Manzur, J. Inorg. Chem. 2004, 43, 6324. (26) He, L.-P.; Chen, T.; Gong, D.; Lai, Z.; Huang, K.-W. Organometallics 2012, 31, 5208. (27) (a) Balkovec, J. M.; Szymonifka, M. J.; Heck, J. V.; Ratcliffe, R. W. J. Antibiot. 1991, 44, 1172. (b) Ulrich, S.; Petitjean, A.; Lehn, J.-M. Eur. J. Inorg. Chem. 2010, 2010, 1913.
has been developed. The reaction proceeds through an unprecedented sequence of N-oxide acylation of 2-alkylpyridine N-oxide with aldehydes followed by a Boekelheide rearrangement. The utility of the method is highlighted by the ability to carry out the desymmetrization of 2,6-lutidine, which provides a more efficient route to very useful Milstein-type pincer ligands. This strategy represents an appealing synthetic method to achieve regio- and chemoselective sp3-functionalization of 2-alkylpyridine.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03446. Experimental procedures, copy of 1H and 13C NMR of all compounds, X-ray analysis of 4 (PDF) Accession Codes
CCDC 1564793 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Jean-François Soulé: 0000-0002-6593-1995 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS C.-S.W. acknowledges the China Scholarship Council (CSC) for a PhD grant. REFERENCES
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DOI: 10.1021/acs.orglett.7b03446 Org. Lett. 2017, 19, 6720−6723
