The poor regioselectivity of the [4 + 2] cycloaddition of 3-azetidinones with internal alkynes bearing two alkyl substituents via nickel-catalyzed carbon–carbon activation is addressed using 1,3-enynes as substrates. The judicious choice of substitution on the enyne enables complementary access to each regioisomer of 3-hydroxy-4,5-alkyl-substituted pyridines, which are important building blocks in medicinal chemistry endeavors

Aissa, C

Barday, M

Halsall, CT

Ho, KYT

Manuel Barday

Kelvin Y. T. Ho

Christopher T. Halsall

Christophe Aïssa

Crossref

Organic Letters

Regioselective Synthesis of 3-Hydroxy-4,5-alkyl-Substituted Pyridines Using 1,3-Enynes as Alkynes Surrogates

The poor regioselectivity
of the [4 + 2] cycloaddition of 3-azetidinones
with internal alkynes bearing two alkyl substituents via nickel-catalyzed
carbon–carbon activation is addressed using 1,3-enynes as substrates.
The judicious choice of substitution on the enyne enables complementary
access to each regioisomer of 3-hydroxy-4,5-alkyl-substituted pyridines,
which are important building blocks in medicinal chemistry endeavors

Manuel Barday (2583856)

Kelvin
Y. T. Ho (2583853)

Christopher T. Halsall (2583859)

Christophe Aïssa (1981003)

The Francis Crick Institute

Regioselective Synthesis of 3‑Hydroxy-4,5-alkyl-Substituted
Pyridines Using 1,3-Enynes as Alkynes Surrogates

University of Liverpool Repository

Organic Letters 2016, 18, 1756–1759 (doi: 10.1021/acs.orglett.6b00451)  Regioselective Synthesis of 3-Hydroxy-4,5-Alkyl-Substituted Pyridines Using 1,3-Enynes as Alkynes Surrogates. Organic Letters 2016, 18, 1756–1759 (doi: 10.1021/acs.orglett.6b00451) Manuel Barday,† Kelvin Y. T. Ho,† Christopher T. Halsall,‡ and Christophe Aïssa*,† † Department of Chemistry, University of Liverpool, Crown Street, L69 7ZD, United Kingdom ‡ Oncology Innovative Medicines Unit, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom * E-mail: aissa@liverpool.ac.uk The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.6b00451. Detailed experimental procedures and characterization of all new compounds (PDF). The authors declare no competing financial interest. ABSTRACT: The poor regioselectivity of the [4+2] cycloaddition of 3-azetidinones with internal alkynes bearing two alkyl substituents via nickel-catalyzed carbon-carbon activation is addressed using 1,3-enynes as substrates. The judicious choice of substitution on the enyne enables complementary access to each regioisomer of 3-hydroxy-4,5-alkyl-substituted pyridines, which are important building blocks in medicinal chemistry endeavors. Alkynes are prominent and versatile building blocks for the synthesis of heterocycles by transition-metal-catalyzed cycloadditions.1 However, poor regioselectivity is often observed in these reactions for internal alkynes bearing two alkyl substituents that are not electronically or sterically strongly biased.2 The nickel-catalyzed [4+2] cycloaddition of N-Ts-3-azetidinone 1 (Ts = para-tolylsulfonyl) and alkyne 2 is a typical example illustrating the lack of selectivity when the steric differentiation between the substituents on the alkyne moiety is limited, and an almost equimolar mixture of the regioisomers of dihydropyridinone 3 was thus obtained (Scheme 1).3 Initial attempts to improve the regioselectivity by varying the ligand remained unsuccessful whilst the conversion to the desired product decreased. Moreover, the regioisomers could not be separated by simple column chromatography. We therefore decided to explore an alternative strategy consisting in using the inexpensive ligand PPh3 and 1,3-enynes as surrogates of alkynes that would otherwise be substituted with two sterically similar alkyl chains R1 and R2 (Scheme 2). The enhanced regioselectivity of the insertion of 1,3-enynes as compared to internal alkynes bearing two alkyl substituents was previously demonstrated for this reaction albeit with only one example,3a,b but we assumed that this preliminary observation could be generalized to other enynes on the basis of theoretical4 and experimental5 studies conducted on the related nickel-catalyzed Organic Letters 2016, 18, 1756–1759 (doi: 10.1021/acs.orglett.6b00451)  reductive coupling of 1,3-enynes with aldehydes. In a sequence inspired by the work previously reported by Fagnou and co-workers for the synthesis of 2,3-aliphatic-substituted pyrroles and indoles,6 we envisioned that the judicious choice of substitution on the 1,3-enyne would enable complementary access to each of the two regioisomers of 3-hydroxy-4,5-alkyl-substituted pyridines, after simple hydrogenation and aromatization steps (Scheme 2).7 Pyridines that have a hydroxyl group in position 3 and two different alkyl groups in positions 4 and 5 are found in compounds that display important biological and pharmaceutical properties and are desirable building blocks in medicinal chemistry endeavors.8 The strategy presented herein offers a valuable alternative to previous approaches to this specific pyridine motif9 and to metal-catalyzed intermolecular reactions of alkynes that afford other pyridine substitution patterns.10 As expected, all 1,3-enynes 4a–4h underwent the nickel-catalyzed [4+2] cycloaddition with good regioselectivity (Table 1, entries 1–8), and the major regioisomer of 5 could be isolated easily in most cases, except for 5b, which explains the moderate yield for this specific example, as opposed to the range of good yields observed for 5a and 5c–5h (67–77%). Although the origin of this effect is not known to us, the average yields of duplicate experiments were consistently higher in some cases (entries 1–5) when the loading of PPh3 was increased from 20 to 30 mol % (see supporting information). Moreover, the directing power of the carbon-carbon double bond of the 1,3-enyne motifs was slightly greater for 1,4-disubstituted enynes (entries  2, 4, and 6–8) than for 2,4-disubsituted (entry 3) or trisubstituted enynes (entries 1 and 5). Nevertheless, this directing effect persisted even with two substituents of similar size on the carbon-carbon triple bond. Thus, we observed a 78:22 regioselectivity for 1,3-enynes 4i and 4j and the major regioisomer could be isolated in 65% and 64% yield, respectively (Scheme 3). The reaction of a mixture of tri- and tetrasubstituted enynes 4k led to 5k in lower yield but with good regioselectivity, an outcome likely influenced by the steric properties of 4k. The substitution of the alkyl group had very limited effect on the regioselectivity (Table 1, entries 2, 4, 6 and 8). The conversion of dihydropyridinones 5a–5h into pyridines 6a–6h was effected in two steps by hydrogenation of the carbon-carbon double bond followed by cleavage of the para-tolylsulfonyl group and concomitant aromatization using DBU9b (Table 1). Thus, the judicious choice of 1,3-enynes 4a–4h enabled a rapid three-step access to each of the two regioisomers of 3-hydroxy-4,5-aliphatic-substituted pyridines 6a/6b, 6c/6d, 6e/6f, and 6g/6h. It was possible to conduct the deprotection/aromatization of compounds 5 prior to hydrogenation, but the resulting pyridines were not suitable substrates for hydrogenation and compounds 6 were thus not obtained. In addition, we also explored an alternative protocol whereby the active Ni catalyst was generated in situ from air-stable pre-catalyst NiBr2(PPh3)2 and Zn. Although initial investigations with 1,3-enyne 4l were promising, the major regioisomer 5l being isolated in 67% yield (eq 1), yields were in general lower from enynes 4a–4f when compared to the Organic Letters 2016, 18, 1756–1759 (doi: 10.1021/acs.orglett.6b00451)  method relying on Ni(cod)2/PPh3 and the regioselectivity was slightly decreased (Table 2). During the preparation of this manuscript, a report disclosed that the combination of NiBr2(PPh3)2 and Zn in MeCN enabled the [4+2] cycloaddition of alkynes and protected azetidin-3-ones.11 However, using this solvent in the case of 4l led to incomplete conversion and 5l was isolated in 14% yield (84:16 regioselectivity). A slightly improved result was obtained by replacing the protective group in 1 with a tert-butoxycarbamoyl group (27%; 90:10 regioselectivity). Initially, the cycloaddition of terminal 1,3-enyne 7 with 1 led to a very sluggish reaction and only very low yields of dihydropyridinone 8 (Table 3, entry 1). It was crucial to use commercially available N-Boc-3-azetidinone 9 (Boc = tert-butoxycarbamoyl) instead of N-Ts-3-azetidinone 1 and to use dioxane as solvent (Entries 2–4) in order to obtain compound 10 in good yield. Increasing the reaction temperature was not beneficial (Entry 5). Importantly, only one regioisomer of 10 was observed. Similarly to 5a–5h, compound 10 could be conveniently converted into 3-hydroxy-pyridine 11 in few steps (eq 2). A single purification by column chromatography was necessary at the end of this sequence and compound 11 was isolated in 57% yield. As previously demonstrated by our group and others, α-substituted 3-azetidinones are good substrates for the [4+2] Ni-catalyzed cycloadditions with alkynes.3 This remains true for 1,3-enynes, as illustrated with 12 (Scheme 4), which is derived from racemic phenylalanine. The reaction of 4l with 12 was slower than with non-substituted 1 but 13 was easily separated from its regioisomer in 64% yield (91:9 regioselectivity). Then, 13 could be rapidly converted into 14 in good yield after hydrogenation followed by cleavage of the para-tolylsulfonyl group and concomitant aromatization using NaHCO3 in a mixture of ethanol and water as alternative to DBU. Although it would in principle be possible to access analogues of 14 from various α-substituted 3-azetidinones, it is more judicious to postpone the functionalization 3-hydroxy-4,5-alkyl-substituted pyridines at a later stage of the sequence. For example, dihydropyridinone 5l was obtained in good yield after treating a mixture of 1 and 4l with 5 mol% of catalyst and separation of the regioisomers (Scheme 5). Then, hydrogenation and cleavage of the para-tolylsulfonyl group with concomitant aromatization gave 15 in 71% over two steps. At this stage, a Mannich reaction with either morpholine or pyrrolidine afforded 2-aminomethyl pyridine derivatives 16 and 17 in excellent yields.12 Alternatively, 15 could be converted into 18, which led to furo[b]pyridine derivative 19 after a Sonogashira cross-coupling.13 In conclusion, we have demonstrated that 1,3-enynes are convenient surrogates of internal alkynes bearing two alkyl substituents in their nickel-catalyzed [4+2] cycloaddition with 3-azetidinones. Thus, the judicious choice of 1,3-enyne pairs enables a facile and Organic Letters 2016, 18, 1756–1759 (doi: 10.1021/acs.orglett.6b00451)  complementary access to each of the two regioisomers of 3-hydroxy-4,5-alkyl-substituted pyridines, after simple hydrogenation and aromatization steps. We are grateful for the financial support from EPSRC (EP/P505615/1 studentship to K. Y. T. H.), the University of Liverpool (Studentship to M. B.) and AstraZeneca. REFERENCES (1) Recent reviews: (a) Varela, J. A.; Saá, C. Synlett 2008, 2571. (b) Satoh, T.; Miura, M. Chem.–Eur. J. 2010, 16, 11212. (c) Shaaban, Mohamed R.; El-Sayed, Refat; Elwahy, Ahmed H. M. Tetrahedron 2011, 67, 6095. (d) Gulevich, A. V.; Dudnik, A. S.; Chernak, N.; Gevorgyan, V. Chem. Rev. 2013, 113, 3084. (e) Egi, M.; Akai, S. Heterocycles 2015, 91, 931. (2) Selected examples: (a) Chatani, N.; Hanafusa, T. J. Org. Chem. 1991, 56, 2166. (b) Crawley, M. L.; Goljer, I.; Jenkins, D. J.; Mehlmann, J. F.; Nogle, L.; Dooley, R.; Mahaney, P. E. Org. Lett. 2006, 8, 5837. (c) Kajita, Y. Kurahashi, T. Matsubara, S. J. Am. Chem. Soc. 2008, 130, 17226. (d) Ooguri, A.; Nakai, K.; Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc. 2009, 131, 13195. (e) Miura, T.; Yamauchi, M.; Murakami, M. Chem. Commun. 2009, 1421. (f)  Stuart, D. R.; Alsabeh, P.; Kuhn, M.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 18326. (g) Duttwyler, S.; Lu, C.; Rheigold, A. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2012, 134, 4064. (h) Villuendas, P.; Urriolabeitia, E. P. J. Org. Chem. 2013, 78, 5254. (i) Kurahashi, T.; Matsubara, S. Acc. Chem. Res. 2015, 48, 1703. (3) (a) Ho. K. Y. T.; Aïssa, C. Chem.–Eur. J. 2012, 18, 3486. (b) Kumar, P.; Louie, J. Org. Lett. 2012, 14, 2026. (c) Ishida, N.; Yuhki, T.; Murakami, M. Org. Lett. 2012, 14, 3898. (4) Liu, P.; McCarren, P.Cheong, P. H.-Y.; Jamison, T. F.; Houk, K. N. J. Am. Chem. Soc. 2010, 132, 2050. (5) (a) Mahandru, G. M.; Liu, G.; Montgomery, J. J. Am. Chem. Soc. 2004, 126, 3698. (b) Miller, K. M.; Luanphaisarmont, Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 4130. (c) Miller, K. M.; Jamison, T. F. Org. Lett. 2005, 7, 3077. (6) Huestis, M. P.; Chan, L.; Stuart, D. R.; Fagnou, K. Angew. Chem., Int. Ed. 2011, 50, 1338. (7) For related reactions with 1,3-dienes, see: (a) Thakur, A.; Facer, M. E.; Louie, J. Angew. Chem. Int. Ed. 2013, 52, 12161; (b) Juliá-Hernández, F.; Ziadi, A.; Nishimura, A.; Martin, R. Angew. Chem. Int. Ed. 2015, 54, 9537. (8) (a) Parvez Alam, M.; Khdour, O. M.; Arce, P. M.; Chen, Y.; Roy, B.; Johnson, W. G.; Dey, S.; Hecht, S. M. Bioorg. Med. Chem. 2014, 22, 4935. (b) Pomytkin, I. A. WO 2014012593 A1. (c) Kim, D.-G.; Kang, Y.; Lee, H.; Lee, E. K.; Nam, T.-g.; Kim, J.-A.; Jeong, B.-S. Eur. J. Med. Chem. 2014, 78, 126. (d) Hoyt, S. B.; Park, M. K.; London, C.; Xiong, Y.; Bennett, D. J.; Cai, J.; Ratcliffe, P.; Cooke, A.; Carswell, E.; MacLean, J.; Saxena, R.; Kulkarni, B. A.; Gupta, A. WO 2012012478 A1. (9) (a) Allevi, P.; Longo, A.; Anastasia, M. Chem. Commun. 1999, 559. (b) Donohoe, T. J. Fishlock, L. P.; Basutto, J. A.; Bower, J. F.; Procopiou, P. A.; Thompson, A. L. Chem. Commun. 2009, 3008. (c) Yoshida, K.; Kawagoe, F.; Hayashi, K.; Horiuchi, S.; Imamoto, T.; Yanagisawa, A. Org. Lett. 2009, 11, 515. (d) Liu, H.; Wang, L.; Tong, X. Chem. Commun. 2011, 47, 12206. (e) Sabot, C.; Oueis, E.; Brune, Organic Letters 2016, 18, 1756–1759 (doi: 10.1021/acs.orglett.6b00451)  X.; Renard, P.-Y. Chem. Commun. 2012, 48, 768. (f) Jouanno, L.-A.; Tognetti, V.; Joubert, L.; Sabot, C.; Renard, P.-Y. Org. Lett. 2013, 15, 2530. (g) Lei, C.-H.; Wang, D.-X.; Zhao, L.; Zhu, J.; Wang, M.-X. J. Am. Chem. Soc. 2013, 135, 4708. (10) Selected examples: (a) Roesh, K. R.; Larock, R. C. J. Org. Chem. 1998, 63, 5306. (b) Fatland, A. W.; Eaton, B. E. Org. Lett. 2000, 2, 3131. (c) Roesch, K. R.; Zhang, H.; Larock, R. C. J. Org. Chem. 2001, 66, 8042. (d) Heller, B.; Sundermann, B.; Buschmann, H.; Drexler, H.-J.; You, J.; Holzgrabe, U.; Heller, E.; Oehme, G. J. Org. Chem. 2002, 67, 4414. (e) Varela, J. A.; Castedo, L.; Saá, C. J. Org. Chem. 2003, 68, 8595. (f) Senaiar, R. S.; Young, D. D.; Deiters, A. D. Chem. Commun. 2006, 1313. (g) Tanaka, K.; Suzuki, N.; Nishida, G. Eur. J. Org. Chem. 2006, 3917. (h) Parthasarathy, K.; Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2008, 10, 325. (i) Colby, D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 3645. (j) Komine, Y.; Tanaka, K. Org. Lett. 2010, 12, 1312. (k) Hyster, T. K.; Rovis, T. Chem. Commun. 2011, 47, 11846. (l) Zhao, M.-N.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H. Chem. Commun. 2012, 48, 8105. (m) Kim, D.-S.; Park, J.-W.; Jun, C.-H. Chem. Commun. 2012, 48, 11334. (n) Sim, Y.-K.; Lee, H.; Park, J.-W.; Kim, D.-S.; Jun, C.-H. Chem. Commun. 2012, 48, 11787. (o) Martin, R. M.; Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2012, 77, 2501. (p) Yamamoto, S.-i.; Okamoto, K.; Murakuso, M.; Kuninobu, Y.; Takai, K. Org. Lett. 2012, 14, 3182. (q) Satoh, Y.; Obora, Y. J. Org. Chem. 2013, 78, 7771. (r) Lee, H.; Sim, Y.-K.; Park, J.-W.; Jun, C.-H. Chem.–Eur. J. 2014, 20, 323. (s) Wu, J.; Xu, W.; Yu, Z.-X.; Wang, J. J. Am. Chem. Soc. 2015, 137, 9489. (t) Zhong, Y.; Spahn, N. A.; Stolley, R. M.; Nguyen, M. H.; Louie, J. Synlett 2015, 307. (11) Thakur, A.; Evangelista, J. L.; Kumar, P.; Louie, J. J. Org. Chem. 2015, 80, 9951. (12) Chi, K.-W.; Ahn, Y. S.; Shim, K. T.; Park, T. J.; Ahn, J. S. Bull. Korean Chem. Soc. 1999, 20, 973. (13) Yamaguchi, M.; Katsumata, H.; Manabe, K. J. Org. Chem. 2013, 78, 9270.   Organic Letters 2016, 18, 1756–1759 (doi: 10.1021/acs.orglett.6b00451)  Scheme 1. Poor regioselectivity in the nickel-catalyzed [4+2] cycloaddition of N-Ts-3-azetidinone and 4-methyl-pent-2-ynea  a The reactions were carried out with 1 (0.22 mmol) and 2 (0.24 mmol). b Conversion determined by 1H NMR. c Determined by 1H NMR of the crude mixture. d Used as 1 M solution in THF. e Made in situ by premixing 1,3-bis(2,4,6-trimethylphenyl)-imidazolium chloride (20 mol %) and tBuOK (20 mol %). f Extensive decomposition of 1 was observed and 3 was not formed.   Organic Letters 2016, 18, 1756–1759 (doi: 10.1021/acs.orglett.6b00451)  Scheme 2. Strategy for the regioselective synthesis of 3-hydroxy-4,5-bisalkyl pyridines    Organic Letters 2016, 18, 1756–1759 (doi: 10.1021/acs.orglett.6b00451)  Table 1. Regioselective synthesis of 3-hydroxy-4,5-alkyl-substituted pyridines using 1,3-enynes as alkynes surrogatesa  a All reactions were carried out with 1 (0.22 mmol), 4 (0.24 mmol), Ni(cod)2 (0.022 mmol), and PPh3 (0.044 mmol) except otherwise noted. b Yield of the isolated major regioisomer only, average of two experiments. c 30 mol % PPh3. d From 1H NMR of the crude mixture. e Yield of isolated 6 after two steps. f Hydrogenation was performed in a flask immersed in a sonication bath for 5 h. g Hydrogenation for 7.5 h. h Hydrogenation for 5 h.   Organic Letters 2016, 18, 1756–1759 (doi: 10.1021/acs.orglett.6b00451)  Scheme 3. Reactions of enynes 4i, 4j and 4ka  a Same reaction conditions as table 1 (entries 1–5).   Organic Letters 2016, 18, 1756–1759 (doi: 10.1021/acs.orglett.6b00451)     Organic Letters 2016, 18, 1756–1759 (doi: 10.1021/acs.orglett.6b00451)  Table 2. Cycloaddition of N-Ts-3-azetidinone with 1,3-enynes 4a–4f catalyzed by NiBr2(PPh3)2/Zna product yield(%)b ratio of regioisomersc 5a 66 85:15 5b 31 91:9 5c 51 85:15 5d 59 91:9 5e 69 87:13 5f 50 91:9 a Reaction conditions as in eq 1. b Yield of the isolated major regioisomer. c From 1H NMR of the crude mixture.   Organic Letters 2016, 18, 1756–1759 (doi: 10.1021/acs.orglett.6b00451)  Table 3. Nickel-catalyzed cycloaddition of 3-azetidinones with a terminal 1,3-enynea  entry 1 or 9 solvent temp (ºC) t (h) yield (%)b  1 1 toluene 60 144 7 2 9 toluene 60 40 40 3 9 THF 60 40 35 4 9 dioxane 60 16 58c 5 9 dioxane 70 16 41 a All reactions were carried out with 1 or 9 (0.22 mmol), 7 (0.24 mmol), Ni(cod)2 (0.022 mmol), and PPh3 (0.066 mmol). b Yield of isolated 8 (entry 1) or 10 (entries 2–5). c Average of two experiments.   Organic Letters 2016, 18, 1756–1759 (doi: 10.1021/acs.orglett.6b00451)     Organic Letters 2016, 18, 1756–1759 (doi: 10.1021/acs.orglett.6b00451)  Scheme 4. Reactions of N-Ts-2-benzyl-3-azetidinone 12  a Yield of isolated major regioisomer only, average of two experiments. b Yield of isolated product after two steps.   Organic Letters 2016, 18, 1756–1759 (doi: 10.1021/acs.orglett.6b00451)  Scheme 5. Further functionalization of 3-hydroxy-4-ethyl-5-isopropylpyridine 15  a Yield of isolated major regioisomer only. b Ratio of regioisomer in the crude reaction mixture. 

https://figshare.com/articles/Regioselective_Synthesis_of_3_Hydroxy_4_5_alkyl_Substituted_Pyridines_Using_1_3_Enynes_as_Alkynes_Surrogates/3144874

Regioselective Synthesis of 3-Hydroxy-4,5-alkyl-Substituted Pyridines Using 1,3-Enynes as Alkynes Surrogates

Abstract

Similar works

Full text

Available Versions

Crossref

The Francis Crick Institute

University of Liverpool Repository