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Mild addition of carbon nucleophiles to pyridine and quinoline N-oxides under different activation conditions
Tetrahedron Letters 55 (2014) 1913–1915
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Mild addition of carbon nucleophiles to pyridine and quinoline N-oxides under different activation conditions Bertrand Lecointre, Rabah Azzouz, Laurent Bischoff ⇑ Normandie Univ, COBRA, UMR 6014 et FR 3038, Univ Rouen, INSA Rouen, CNRS, IRCOF, 1 rue Tesnière, 76821 Mont Saint Aignan Cedex, France
a r t i c l e
i n f o
Article history: Received 26 December 2013 Revised 23 January 2014 Accepted 28 January 2014 Available online 6 February 2014
a b s t r a c t In the course of our syntheses of functionalised pyridine and quinoline derivatives, we examined the reactivities of pyridine and quinoline N-oxides towards the nucleophilic addition of acidic carbon derivatives. Different activating reagents were used, such as PyBroP, triflic anhydride and a combination of pyrrolidine phosphoramide and triflic anhydride. Ó 2014 Elsevier Ltd. All rights reserved.
Keywords: Pyridine Quinoline N-Oxide C-nucleophiles Coupling agents
Introduction Pyridine and quinoline are very common motifs in bioactive compounds and various quinoline derivatives are known to display a broad range of pharmacological properties, which enable them to be used as anti-cancer,1 anti-HIV2 and anti-hypertensive3 agents. During the last decade, much effort has been devoted to the discovery of mild activation methods affording the introduction of various nucleophiles at C-2 of pyridine and quinoline. The well-known Chichibabin4a,b reaction, relying on the release of a hydride leaving group, involves harsh basic conditions, thus limiting the scope of the reaction. However, a combined oxidation-electrophilic activation process involving N-oxides has been developed by several groups. In this way, the electrophilic activation of the corresponding N-oxides affords an efficient addition of nucleophiles at C-2, followed by the loss of proton and concomitant re-aromatisation of the heterocycle.5a,b These methods offer two main advantages, since the preliminary oxidation step generally occurs smoothly, and on the other hand the mild conditions employed for the N-oxide activation provide a broad scope of both substrates and nucleophiles. Initially, most groups were interested in 2-amino azine compounds, as they provide interesting scaffolds for SAR studies. A first report in 19696 showed that imidoyl chlorides could be used in the straight transformation of N-oxides into 2-amidopyridines, ⇑ Corresponding author. Tel.: +33 235522903; fax: +33 0235522962. E-mail address: [email protected] (L. Bischoff). http://dx.doi.org/10.1016/j.tetlet.2014.01.134 0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
via an intramolecular process. A further exploration of this field showed that imidoyl chlorides could be easily generated using oxalyl chloride,7a and another similar process afforded amidation with acyl isocyanates.7b N-Oxide rearrangement can also occur under harsh conditions such as heating in acetic anhydride at 140 °C, leading to the 2-acetoxy compounds.8 More recently, good results were obtained with electrophiles exhibiting higher reactivities, especially non-carboxylic acid chlorides or anhydrides, such as sulfonic acid or phosphoric acid derivatives. Sulfonic anhydrides are efficient for the incorporation of heteroatoms at C2, however side-reactions such as the addition at C4, or reaction between the nucleophile and the activating agent can prevail. This difficulty could be overcome using excess tert-butylamine in the presence of Ts2O in trifluorotoluene.9 Thus, using Ts2O/t-BuNH2, 2-aminopyridines were obtained after deprotection. On the other hand, if the leaving group exhibits a sufficient nucleophilic character, it can be used directly under its tosylated form, for example N-tosyl azoles,10 so as to avoid competitive halide addition. Most recently, an efficient bromination of quinolines and other fused azines was proposed by Baran,11 using Ts2O as the activating agent and TBAB as the bromide source. Using phosphorus reagents, PyBroP seems to be amongst the most efficient reagents, while affording mild reaction conditions hence has an interesting compatibility with most moieties and protective groups. Owing to this reagent, Londregan et al.12a,b showed that various nucleophiles such as amines, thiols, phenols and stabilised carbanions could undergo nucleophilic additions at C2, starting from pyridine or quinoline substrates.
1914
B. Lecointre et al. / Tetrahedron Letters 55 (2014) 1913–1915
Results and discussion In the course of our syntheses of pyridine derivatives, we were interested in broadening the scope of these reactions, especially by studying other carbon nucleophiles, leading to precursors of more complex structures. We also checked the influence of the activating agent on the C2/C4 selectivity with very soft nucleophiles, using in-situ generated tris-pyrrolidino-phosphonium triflate or PyTof. Our first experiments were carried out with commerciallyavailable pyridine N-oxide. Under the conditions described by Londregan et al., a large panel of nucleophiles was employed. First reactions running with b-dicarbonyl compounds afforded efficient addition of the carbon nucleophiles onto pyridine N-oxide. As listed in Table 1, the reaction of various carbon nucleophiles under PyBrop activation14 proceeded smoothly. The use of dichloromethane confirmed the regioselectivities obtained by Londregan et al. (entries 3–5), whereas toluene afforded substantial amounts of addition at C4 (entries 1 and 2). Pleasingly, in the case of Table 1 Influence of the activating agent and solvents on the regioselectivity Entry
Coupling agent
Solvent
Major isomer
Minor isomer N
1
PyBrOP
Toluene
CO2 Et
CO2 Et
N
CO2 Et
CO2 Et
3e, 8%
1a, 48% O 2
PyBrOP
Toluene
N
O
O
N O
O
O
O
1b, 60%
O
3f, 18%
O 3
PyBrOP
CH2Cl2
N
Ph CO2 Et
1c, 72% 4
PyBrOP
CH2Cl2
5
PyBrOP
CH2Cl2
PhO 2S
SO 2Ph
1d, 85 % PhO 2S
SO 2Ph F
1e, 100 %
6
PyBrOP
CH2Cl2
7 8 9 10 11
PyBrOP PyBrOP PyBrOP PyBrOP PyTof
Dioxane Et2O CH3CN Toluene CH2Cl2
CO 2Et CO2Et CO2Et
N
N
CO 2Et CO2Et CO2Et
2a, 69% 61% 28% 33% 45% 60%
3a, 29% 39% 20% 7% 35% 0%
N 12
PyBrOP
Toluene
N O
CO2Et
CO2Et CO2Et
3b, 20%
2b, 38% O 13
PyBrOP
Toluene
N O
CO2Et
N PyBrOP
Toluene
N
O
N O
CO2Et CO2Et
2d, 48%
CO2Et
3c, 26%
2c, 52%
14
CO2Et
O
disulfonyl compounds, very good yields were obtained, especially with a fluorinated analogue which gave a quantitative yield (entry 5). This substituent is an interesting precursor of the CH2F synthon13 after reductive cleavage of both phenylsulfonyl groups (Scheme 1). We further examined the reactivity of very soft, highly stabilised carbon nucleophiles, such as tricarbonyl compounds. Although previous examples had shown a good selectivity for the C2 position, those nucleophiles yielded substantial amounts of C4 addition. At first, we used dichloromethane as the solvent, and further examined the effects of other common solvents on the outcome of the reaction. We first examined the regioselectivities obtained with H-C(CO2Et)3 as the nucleophile (entries 6–11). CH2Cl2 gave a smooth, nearly quantitative reaction, though with a 69:29 ratio in favour of the C2 attack. Running the same reaction in CDCl3 (for NMR monitoring) gave the same regioselectivity. Using dioxane resulted in more addition at C4, whereas ether was essentially unselective (3:2 ratio), though with a lower yield. A more polar solvent such as acetonitrile gave a better C2 selectivity, however with a poor yield. Finally, we tried to enhance the reactivity of the activating agent, by preparing the triflate analogue of PyBroP. For this purpose, tris(pyrrolidino)phosphoramide was treated with triflic anhydride, and the resulting solution in dichloromethane was used for the activation. Using this reagent (that we named ‘PyTof’), we were pleased to obtain an excellent regioselectivity at C2, although with in a moderate 60% yield (entry 11). As far as the addition at C4 is concerned, the highest regioselectivity for this position was observed using toluene (entry 10). As both isomers are easy to separate by means of flash chromatography, we could obtain each of them in a pure form. We then tried to use toluene with other nucleophiles; unfortunately, none of them afforded a good selectivity for the C4 position (entries 12–14). We finally used compound 1a as the nucleophile, leading to a di-pyridine compound (entry 14). In addition, quinoline N-oxide (Table 2) afforded moderate to good yields upon treatment with activating agents in dichloromethane. Good regioselectivities were obtained, since no addition at C4 was observed. In some cases, Tf2O15 gave the best yields (entries 4, 6, 8), except with Meldrum’s acid that gave a better yield using PyTof,15 a milder activation reagent leading to less decomposition. Interestingly, some compounds prepared previously from pyridine N-oxide could also serve as nucleophiles in this reaction, thus giving access to many possibilities of molecules bearing both pyridine and/or quinoline attached to the quaternary center (Table 2, entry 14). Finally, we explored the possibility of preparing di-substituted compounds by means of both additions at C2 and C4. As depicted in Scheme 2, both compounds 6 and 7, resulting from the N-oxidation of 2a and 3a isomers respectively, with urea-hydrogen peroxide/TFAA,16 were reacted with H-C(CO2Et)3 under PyBroP activation. The results obtained showed that no addition occurred starting from the 2-substituted isomer, while the 4-substituted isomer gave an excellent yield of compound 8. This confirmed that the initial activation step is very sensitive to steric hindrance at C2, showing the limitation of this reaction with bulky substituents. In this way, when two different functional groups are required at C2 and C4, the synthesis should start with the C4 addition, which is favored using toluene as the solvent.
N
N CO2Et CO2Et
3d, 38 %
Nu Nu-H, coupling reagent N+ O-
i-Pr 2NEt, solvent
N
Nu
1a-e; 2a-d
N 3a-f
Scheme 1. Activation of pyridine N-oxide and addition of carbon nucleophiles.
B. Lecointre et al. / Tetrahedron Letters 55 (2014) 1913–1915 Table 2 Activation of quinoline N-oxide Entry
Coupling agent
Solvent
1
PyBrOP
CH2Cl2
2 3 4 5
PyClOP Ms2O Tf2O PyTof
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2
6
Tf2O
Product
CO2 Et CO2 Et CO Et
N 40 34 69 42
4a, 55 %
(%) (%) (%) (%)
4b, 50 %
CH2Cl2
CO 2Et
N PyBrOP
CH2Cl2
24 (%)
4c, 72 %
O 8
9 10
Tf2O
CH2Cl2
PyBrOP PyTof
CH2Cl2 CH2Cl2
N
Ph CO2Et
72 (%) 38 (%)
Tf2O
CH2Cl2
12 13
PyBrOP PyTof
CH2Cl2 CH2Cl2
35 % O
N O
O
25 (%) 57 (%)
N 14
N
CH2Cl2
PyBrOP
SO2 Ph SO2 Ph
4e, 64 %
H-C(CO2 Et) 3 N+ O-
N+ O-
C(CO2 Et) 3
no reaction
PyBrop, DIEA
6 SO2 Ph
PhO 2S
SO 2Ph
no reaction
PyBrop, DIEA
SO 2Ph 10
C(CO 2Et)3
C(CO 2Et)3
H-C(CO2 Et)3 N+ O- 7
PyBrop, DIEA
N
C(CO2Et)3
8 (85%) UHP, TFAA Acetonitrile C(CO 2Et)3
no reaction
H-C(CO2 Et)3 PyBrop, DIEA
Acknowledgments We thank the INTERREG ISCE:Chem (Ref: 1917/4061), this program was selected under the European Cross-border Cooperation Programme INTERREG IV A France (Channel)—England, co-funded by the ERDF. The Centre Universitaire Normand de Chimie Organique ‘Crunch’ network is also gratefully acknowledged.
Supplementary data (details experimental procedure and characterisation data of selected compounds and copies of 1H NMR and 13 C NMR spectra) associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.01.134. References and notes
O 11
Good selectivities at C2 could be obtained with PyTof reagent; however we could not reach high selectivities for the C4 substitution. These highly functionalised carbon substituents open the way towards more complex pyridine and quinoline structures.
Supplementary data
CO2Et 7
1915
+
N C(CO2Et)3 O9 (23%)
Scheme 2. Disubstituted compounds.
The second introduction of another nucleophile at C2 can be achieved under classical conditions. Conclusion In summary, we have examined a wide range of carbon nucleophiles for their introduction onto pyridine and quinoline nuclei.
1. Tsotinis, A.; Vlachou, M.; Zouroudis, S.; Jeney, A.; Timar, F.; Thruston, D. E.; Roussakis, C. Lett. Drug Des. Discovery 2005, 2, 189–192. 2. Franck, X.; Fournet, A.; Prina, E.; Mahieux, R.; Hocquemiller, R.; Figadère, B. Bioorg. Med. Chem. Lett. 2004, 14, 3635–3638. 3. Muruganantham, N.; Sivakumar, R.; Anbalagan, N.; Gunasekaran, V.; Leonard, J. T. Biol. Pharm. Bull. 2004, 27, 1683–1687. 4. (a) Chichibabin, A. E. Zhurnal Russkago Fiziko-Khimicheskago Obshchestva 1914, 46, 1216–1236; (b) Sagitullin, R. S.; Shkil’, G. P.; Nosonova, I. I.; Ferber, A. A. Chem. Heterocycl. Compd. 1996, 32, 127–140. 5. Yamanaka, H. Heterocycles 1992, 33, 1; (b) Yamanaka, H. Chem. Pharm. Bull. 1988, 36, 2244–2247. 6. Abramovich, R. A.; Singer, G. M. J. Am. Chem. Soc. 1969, 91, 5672–5673. 7. (a) Manley, P. J.; Bilodeau, M. T. Org. Lett. 2002, 4, 3127; (b) Couturier, M.; Caron, L.; Tumidajski, S.; Jones, K.; White, T. D. Org. Lett. 2006, 8, 1929–1932. 8. Kelly, T. R.; Bridger, G. J.; Zhao, C. J. Am. Chem. Soc. 1990, 112, 8024–8034. 9. Yin, J.; Xiang, B.; Huffman, M. A.; Raab, C. E.; Davies, I. W. J. Org. Chem. 2007, 72, 4554–4557. 10. Keith, J. M. J. Org. Chem. 2010, 75, 2722–2725. 11. Wengryniuk, S. E.; Weickgenannt, A.; Reiher, C.; Strotman, N. A.; Chen, K.; Eastgate, M. D.; Baran, P. S. Org. Lett. 2013, 15, 792–795. 12. (a) Londregan, A. T.; Jennings, S.; Wei, L. Org. Lett. 2010, 12, 5254–5257; (b) Londregan, A. T.; Jennings, S.; Wei, L. Org. Lett. 2011, 13, 1840–1843. 13. Prakash, G. K. S.; Chacko, S.; Alconcel, S.; Stewart, T.; Mathew, T.; Olah, G. A. Angew. Chem., Int. Ed. 2007, 46, 4933–4936. 14. Typical procedure with PyBrOP reagent. To a solution of PyBrOP (318 mg, 0.68 mmol, 1.3 equiv), pyridine N-oxide (50 mg, 0.53 mmol, 1 equiv) and nucleophile (0.66 mmol, 1.25 equiv) in appropriate solvent (1 mL, 0.53 M), iPr2EtN (300 lL, 1.97 mmol, 3.75 equiv) was added. The reaction was stirred at rt overnight. The reaction medium was concentrated in vacuo and the residue was purified by flash chromatography, using a mixture of petroleum ether and ethyl acetate, generally 4:1 to 3:2. 15. Typical procedure with Tf2O reagent. A solution of quinoline N-oxide (100 mg, 0.69 mmol, 1 equiv), iPr2EtN (450 lL, 0.89 mmol, 3.75 equiv) and nucleophile (0.65 mmol, 1.25 equiv) in dichloromethane (2 mL) was cooled to 78 °C and Tf2O (150 lL, 894 mmol, 1.3 equiv) was added dropwise. The mixture was stirred at 78°C for 30 min and allowed to warm to rt overnight. The reaction medium was concentrated in vacuo and the residue was purified by flash chromatography, using a mixture of petroleum ether and ethyl acetate, generally 4:1 to 3:2. Typical procedure for the preparation and use of PyTof reagent. A solution of trispyrrolidino-phosphoramide (2 mmol) in dichloromethane (1 mL) was cooled to 78 °C and Tf2O (2.1 equiv) was added dropwise. After stirring at 78 °C for 30 min then rt for 15 min, the resulting solution (2 mmol in PyTof) was then treated with a solution consisting of pyridine or quinoline N-oxide (1 mmol), carbon nucleophile (1.25 mmol) and dichloromethane (1 mL). The mixture was cooled to 78 °C and iPr2EtN (3.75 equiv) was added dropwise. The mixture was stirred at 78 °C for 30 min and allowed to warm to rt overnight. The reaction medium was concentrated in vacuo and the residue was purified by flash chromatography, using a mixture of petroleum ether and ethyl acetate, generally 4:1 to 3:2. 16. Cooper, M. S.; Harry Heaney, H.; Newbold, A. J.; Sanderson, W. R. Synlett 1990, 533–535. General procedure for the N-oxidation of pyridine. To a suspension of pyridine derivative (1 equiv) and urea-hydrogen peroxide (2.1 equiv) in acetonitrile at 0 °C, trifluoroacetic anhydride (2 equiv) was added dropwise. The mixture was stirred 1 h at 0 °C. The reaction medium was concentrated in vacuo and the residue purified by flash chromatography.
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Mild addition of carbon nucleophiles to pyridine and quinoline N-oxides under different activation conditions Bertrand Lecointre, Rabah Azzouz, Laurent Bischoff ⇑ Normandie Univ, COBRA, UMR 6014 et FR 3038, Univ Rouen, INSA Rouen, CNRS, IRCOF, 1 rue Tesnière, 76821 Mont Saint Aignan Cedex, France
a r t i c l e
i n f o
Article history: Received 26 December 2013 Revised 23 January 2014 Accepted 28 January 2014 Available online 6 February 2014
a b s t r a c t In the course of our syntheses of functionalised pyridine and quinoline derivatives, we examined the reactivities of pyridine and quinoline N-oxides towards the nucleophilic addition of acidic carbon derivatives. Different activating reagents were used, such as PyBroP, triflic anhydride and a combination of pyrrolidine phosphoramide and triflic anhydride. Ó 2014 Elsevier Ltd. All rights reserved.
Keywords: Pyridine Quinoline N-Oxide C-nucleophiles Coupling agents
Introduction Pyridine and quinoline are very common motifs in bioactive compounds and various quinoline derivatives are known to display a broad range of pharmacological properties, which enable them to be used as anti-cancer,1 anti-HIV2 and anti-hypertensive3 agents. During the last decade, much effort has been devoted to the discovery of mild activation methods affording the introduction of various nucleophiles at C-2 of pyridine and quinoline. The well-known Chichibabin4a,b reaction, relying on the release of a hydride leaving group, involves harsh basic conditions, thus limiting the scope of the reaction. However, a combined oxidation-electrophilic activation process involving N-oxides has been developed by several groups. In this way, the electrophilic activation of the corresponding N-oxides affords an efficient addition of nucleophiles at C-2, followed by the loss of proton and concomitant re-aromatisation of the heterocycle.5a,b These methods offer two main advantages, since the preliminary oxidation step generally occurs smoothly, and on the other hand the mild conditions employed for the N-oxide activation provide a broad scope of both substrates and nucleophiles. Initially, most groups were interested in 2-amino azine compounds, as they provide interesting scaffolds for SAR studies. A first report in 19696 showed that imidoyl chlorides could be used in the straight transformation of N-oxides into 2-amidopyridines, ⇑ Corresponding author. Tel.: +33 235522903; fax: +33 0235522962. E-mail address: [email protected] (L. Bischoff). http://dx.doi.org/10.1016/j.tetlet.2014.01.134 0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
via an intramolecular process. A further exploration of this field showed that imidoyl chlorides could be easily generated using oxalyl chloride,7a and another similar process afforded amidation with acyl isocyanates.7b N-Oxide rearrangement can also occur under harsh conditions such as heating in acetic anhydride at 140 °C, leading to the 2-acetoxy compounds.8 More recently, good results were obtained with electrophiles exhibiting higher reactivities, especially non-carboxylic acid chlorides or anhydrides, such as sulfonic acid or phosphoric acid derivatives. Sulfonic anhydrides are efficient for the incorporation of heteroatoms at C2, however side-reactions such as the addition at C4, or reaction between the nucleophile and the activating agent can prevail. This difficulty could be overcome using excess tert-butylamine in the presence of Ts2O in trifluorotoluene.9 Thus, using Ts2O/t-BuNH2, 2-aminopyridines were obtained after deprotection. On the other hand, if the leaving group exhibits a sufficient nucleophilic character, it can be used directly under its tosylated form, for example N-tosyl azoles,10 so as to avoid competitive halide addition. Most recently, an efficient bromination of quinolines and other fused azines was proposed by Baran,11 using Ts2O as the activating agent and TBAB as the bromide source. Using phosphorus reagents, PyBroP seems to be amongst the most efficient reagents, while affording mild reaction conditions hence has an interesting compatibility with most moieties and protective groups. Owing to this reagent, Londregan et al.12a,b showed that various nucleophiles such as amines, thiols, phenols and stabilised carbanions could undergo nucleophilic additions at C2, starting from pyridine or quinoline substrates.
1914
B. Lecointre et al. / Tetrahedron Letters 55 (2014) 1913–1915
Results and discussion In the course of our syntheses of pyridine derivatives, we were interested in broadening the scope of these reactions, especially by studying other carbon nucleophiles, leading to precursors of more complex structures. We also checked the influence of the activating agent on the C2/C4 selectivity with very soft nucleophiles, using in-situ generated tris-pyrrolidino-phosphonium triflate or PyTof. Our first experiments were carried out with commerciallyavailable pyridine N-oxide. Under the conditions described by Londregan et al., a large panel of nucleophiles was employed. First reactions running with b-dicarbonyl compounds afforded efficient addition of the carbon nucleophiles onto pyridine N-oxide. As listed in Table 1, the reaction of various carbon nucleophiles under PyBrop activation14 proceeded smoothly. The use of dichloromethane confirmed the regioselectivities obtained by Londregan et al. (entries 3–5), whereas toluene afforded substantial amounts of addition at C4 (entries 1 and 2). Pleasingly, in the case of Table 1 Influence of the activating agent and solvents on the regioselectivity Entry
Coupling agent
Solvent
Major isomer
Minor isomer N
1
PyBrOP
Toluene
CO2 Et
CO2 Et
N
CO2 Et
CO2 Et
3e, 8%
1a, 48% O 2
PyBrOP
Toluene
N
O
O
N O
O
O
O
1b, 60%
O
3f, 18%
O 3
PyBrOP
CH2Cl2
N
Ph CO2 Et
1c, 72% 4
PyBrOP
CH2Cl2
5
PyBrOP
CH2Cl2
PhO 2S
SO 2Ph
1d, 85 % PhO 2S
SO 2Ph F
1e, 100 %
6
PyBrOP
CH2Cl2
7 8 9 10 11
PyBrOP PyBrOP PyBrOP PyBrOP PyTof
Dioxane Et2O CH3CN Toluene CH2Cl2
CO 2Et CO2Et CO2Et
N
N
CO 2Et CO2Et CO2Et
2a, 69% 61% 28% 33% 45% 60%
3a, 29% 39% 20% 7% 35% 0%
N 12
PyBrOP
Toluene
N O
CO2Et
CO2Et CO2Et
3b, 20%
2b, 38% O 13
PyBrOP
Toluene
N O
CO2Et
N PyBrOP
Toluene
N
O
N O
CO2Et CO2Et
2d, 48%
CO2Et
3c, 26%
2c, 52%
14
CO2Et
O
disulfonyl compounds, very good yields were obtained, especially with a fluorinated analogue which gave a quantitative yield (entry 5). This substituent is an interesting precursor of the CH2F synthon13 after reductive cleavage of both phenylsulfonyl groups (Scheme 1). We further examined the reactivity of very soft, highly stabilised carbon nucleophiles, such as tricarbonyl compounds. Although previous examples had shown a good selectivity for the C2 position, those nucleophiles yielded substantial amounts of C4 addition. At first, we used dichloromethane as the solvent, and further examined the effects of other common solvents on the outcome of the reaction. We first examined the regioselectivities obtained with H-C(CO2Et)3 as the nucleophile (entries 6–11). CH2Cl2 gave a smooth, nearly quantitative reaction, though with a 69:29 ratio in favour of the C2 attack. Running the same reaction in CDCl3 (for NMR monitoring) gave the same regioselectivity. Using dioxane resulted in more addition at C4, whereas ether was essentially unselective (3:2 ratio), though with a lower yield. A more polar solvent such as acetonitrile gave a better C2 selectivity, however with a poor yield. Finally, we tried to enhance the reactivity of the activating agent, by preparing the triflate analogue of PyBroP. For this purpose, tris(pyrrolidino)phosphoramide was treated with triflic anhydride, and the resulting solution in dichloromethane was used for the activation. Using this reagent (that we named ‘PyTof’), we were pleased to obtain an excellent regioselectivity at C2, although with in a moderate 60% yield (entry 11). As far as the addition at C4 is concerned, the highest regioselectivity for this position was observed using toluene (entry 10). As both isomers are easy to separate by means of flash chromatography, we could obtain each of them in a pure form. We then tried to use toluene with other nucleophiles; unfortunately, none of them afforded a good selectivity for the C4 position (entries 12–14). We finally used compound 1a as the nucleophile, leading to a di-pyridine compound (entry 14). In addition, quinoline N-oxide (Table 2) afforded moderate to good yields upon treatment with activating agents in dichloromethane. Good regioselectivities were obtained, since no addition at C4 was observed. In some cases, Tf2O15 gave the best yields (entries 4, 6, 8), except with Meldrum’s acid that gave a better yield using PyTof,15 a milder activation reagent leading to less decomposition. Interestingly, some compounds prepared previously from pyridine N-oxide could also serve as nucleophiles in this reaction, thus giving access to many possibilities of molecules bearing both pyridine and/or quinoline attached to the quaternary center (Table 2, entry 14). Finally, we explored the possibility of preparing di-substituted compounds by means of both additions at C2 and C4. As depicted in Scheme 2, both compounds 6 and 7, resulting from the N-oxidation of 2a and 3a isomers respectively, with urea-hydrogen peroxide/TFAA,16 were reacted with H-C(CO2Et)3 under PyBroP activation. The results obtained showed that no addition occurred starting from the 2-substituted isomer, while the 4-substituted isomer gave an excellent yield of compound 8. This confirmed that the initial activation step is very sensitive to steric hindrance at C2, showing the limitation of this reaction with bulky substituents. In this way, when two different functional groups are required at C2 and C4, the synthesis should start with the C4 addition, which is favored using toluene as the solvent.
N
N CO2Et CO2Et
3d, 38 %
Nu Nu-H, coupling reagent N+ O-
i-Pr 2NEt, solvent
N
Nu
1a-e; 2a-d
N 3a-f
Scheme 1. Activation of pyridine N-oxide and addition of carbon nucleophiles.
B. Lecointre et al. / Tetrahedron Letters 55 (2014) 1913–1915 Table 2 Activation of quinoline N-oxide Entry
Coupling agent
Solvent
1
PyBrOP
CH2Cl2
2 3 4 5
PyClOP Ms2O Tf2O PyTof
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2
6
Tf2O
Product
CO2 Et CO2 Et CO Et
N 40 34 69 42
4a, 55 %
(%) (%) (%) (%)
4b, 50 %
CH2Cl2
CO 2Et
N PyBrOP
CH2Cl2
24 (%)
4c, 72 %
O 8
9 10
Tf2O
CH2Cl2
PyBrOP PyTof
CH2Cl2 CH2Cl2
N
Ph CO2Et
72 (%) 38 (%)
Tf2O
CH2Cl2
12 13
PyBrOP PyTof
CH2Cl2 CH2Cl2
35 % O
N O
O
25 (%) 57 (%)
N 14
N
CH2Cl2
PyBrOP
SO2 Ph SO2 Ph
4e, 64 %
H-C(CO2 Et) 3 N+ O-
N+ O-
C(CO2 Et) 3
no reaction
PyBrop, DIEA
6 SO2 Ph
PhO 2S
SO 2Ph
no reaction
PyBrop, DIEA
SO 2Ph 10
C(CO 2Et)3
C(CO 2Et)3
H-C(CO2 Et)3 N+ O- 7
PyBrop, DIEA
N
C(CO2Et)3
8 (85%) UHP, TFAA Acetonitrile C(CO 2Et)3
no reaction
H-C(CO2 Et)3 PyBrop, DIEA
Acknowledgments We thank the INTERREG ISCE:Chem (Ref: 1917/4061), this program was selected under the European Cross-border Cooperation Programme INTERREG IV A France (Channel)—England, co-funded by the ERDF. The Centre Universitaire Normand de Chimie Organique ‘Crunch’ network is also gratefully acknowledged.
Supplementary data (details experimental procedure and characterisation data of selected compounds and copies of 1H NMR and 13 C NMR spectra) associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.01.134. References and notes
O 11
Good selectivities at C2 could be obtained with PyTof reagent; however we could not reach high selectivities for the C4 substitution. These highly functionalised carbon substituents open the way towards more complex pyridine and quinoline structures.
Supplementary data
CO2Et 7
1915
+
N C(CO2Et)3 O9 (23%)
Scheme 2. Disubstituted compounds.
The second introduction of another nucleophile at C2 can be achieved under classical conditions. Conclusion In summary, we have examined a wide range of carbon nucleophiles for their introduction onto pyridine and quinoline nuclei.
1. Tsotinis, A.; Vlachou, M.; Zouroudis, S.; Jeney, A.; Timar, F.; Thruston, D. E.; Roussakis, C. Lett. Drug Des. Discovery 2005, 2, 189–192. 2. Franck, X.; Fournet, A.; Prina, E.; Mahieux, R.; Hocquemiller, R.; Figadère, B. Bioorg. Med. Chem. Lett. 2004, 14, 3635–3638. 3. Muruganantham, N.; Sivakumar, R.; Anbalagan, N.; Gunasekaran, V.; Leonard, J. T. Biol. Pharm. Bull. 2004, 27, 1683–1687. 4. (a) Chichibabin, A. E. Zhurnal Russkago Fiziko-Khimicheskago Obshchestva 1914, 46, 1216–1236; (b) Sagitullin, R. S.; Shkil’, G. P.; Nosonova, I. I.; Ferber, A. A. Chem. Heterocycl. Compd. 1996, 32, 127–140. 5. Yamanaka, H. Heterocycles 1992, 33, 1; (b) Yamanaka, H. Chem. Pharm. Bull. 1988, 36, 2244–2247. 6. Abramovich, R. A.; Singer, G. M. J. Am. Chem. Soc. 1969, 91, 5672–5673. 7. (a) Manley, P. J.; Bilodeau, M. T. Org. Lett. 2002, 4, 3127; (b) Couturier, M.; Caron, L.; Tumidajski, S.; Jones, K.; White, T. D. Org. Lett. 2006, 8, 1929–1932. 8. Kelly, T. R.; Bridger, G. J.; Zhao, C. J. Am. Chem. Soc. 1990, 112, 8024–8034. 9. Yin, J.; Xiang, B.; Huffman, M. A.; Raab, C. E.; Davies, I. W. J. Org. Chem. 2007, 72, 4554–4557. 10. Keith, J. M. J. Org. Chem. 2010, 75, 2722–2725. 11. Wengryniuk, S. E.; Weickgenannt, A.; Reiher, C.; Strotman, N. A.; Chen, K.; Eastgate, M. D.; Baran, P. S. Org. Lett. 2013, 15, 792–795. 12. (a) Londregan, A. T.; Jennings, S.; Wei, L. Org. Lett. 2010, 12, 5254–5257; (b) Londregan, A. T.; Jennings, S.; Wei, L. Org. Lett. 2011, 13, 1840–1843. 13. Prakash, G. K. S.; Chacko, S.; Alconcel, S.; Stewart, T.; Mathew, T.; Olah, G. A. Angew. Chem., Int. Ed. 2007, 46, 4933–4936. 14. Typical procedure with PyBrOP reagent. To a solution of PyBrOP (318 mg, 0.68 mmol, 1.3 equiv), pyridine N-oxide (50 mg, 0.53 mmol, 1 equiv) and nucleophile (0.66 mmol, 1.25 equiv) in appropriate solvent (1 mL, 0.53 M), iPr2EtN (300 lL, 1.97 mmol, 3.75 equiv) was added. The reaction was stirred at rt overnight. The reaction medium was concentrated in vacuo and the residue was purified by flash chromatography, using a mixture of petroleum ether and ethyl acetate, generally 4:1 to 3:2. 15. Typical procedure with Tf2O reagent. A solution of quinoline N-oxide (100 mg, 0.69 mmol, 1 equiv), iPr2EtN (450 lL, 0.89 mmol, 3.75 equiv) and nucleophile (0.65 mmol, 1.25 equiv) in dichloromethane (2 mL) was cooled to 78 °C and Tf2O (150 lL, 894 mmol, 1.3 equiv) was added dropwise. The mixture was stirred at 78°C for 30 min and allowed to warm to rt overnight. The reaction medium was concentrated in vacuo and the residue was purified by flash chromatography, using a mixture of petroleum ether and ethyl acetate, generally 4:1 to 3:2. Typical procedure for the preparation and use of PyTof reagent. A solution of trispyrrolidino-phosphoramide (2 mmol) in dichloromethane (1 mL) was cooled to 78 °C and Tf2O (2.1 equiv) was added dropwise. After stirring at 78 °C for 30 min then rt for 15 min, the resulting solution (2 mmol in PyTof) was then treated with a solution consisting of pyridine or quinoline N-oxide (1 mmol), carbon nucleophile (1.25 mmol) and dichloromethane (1 mL). The mixture was cooled to 78 °C and iPr2EtN (3.75 equiv) was added dropwise. The mixture was stirred at 78 °C for 30 min and allowed to warm to rt overnight. The reaction medium was concentrated in vacuo and the residue was purified by flash chromatography, using a mixture of petroleum ether and ethyl acetate, generally 4:1 to 3:2. 16. Cooper, M. S.; Harry Heaney, H.; Newbold, A. J.; Sanderson, W. R. Synlett 1990, 533–535. General procedure for the N-oxidation of pyridine. To a suspension of pyridine derivative (1 equiv) and urea-hydrogen peroxide (2.1 equiv) in acetonitrile at 0 °C, trifluoroacetic anhydride (2 equiv) was added dropwise. The mixture was stirred 1 h at 0 °C. The reaction medium was concentrated in vacuo and the residue purified by flash chromatography.