Metal-free regioselective C-3 nitration of quinoline N-oxides with tert-butyl nitrite

Abstract

A direct and eco-friendly nitration methodology to synthesize 3-nitroquinoline N-oxides from quinoline N-oxides using tert-butyl nitrite as both the nitro source and oxidant has been developed. Although this reaction undergoes a free radical process, it exhibits high regioselectivity and can be smoothly scaled up to gram scale.

---

Aromatic nitro compounds are important and versatile building blocks in synthetic organic chemistry, and their derivatives are widely utilized in various fields such as pharmaceuticals, dyes, explosives, plastics, and materials.^1,2 Traditional nitration methods often use an excess of nitric acid or its mixture with sulfuric acid or dinitrogen pentoxide, which then result in limited functional group tolerance under such harsh conditions. Moreover, undesirable by-products and acidic waste are generated by these procedures. Recently, nitro reactions have developed rapidly with the emergence of new nitrating agents such as nitrate,³ nitrite salts⁴ and tert-butyl nitrite (TBN).⁵

Recently, direct C–H nitration of olefins and arenes has been developed rapidly. Accordingly, various nitroolefins were synthesized from olefins with different nitrating agents (Scheme 1, Route A).⁶ Besides, direct C–H nitration of arenes could also be realized through the following two pathways: (1) Pd, Cu or Rh-catalyzed aromatic C–H nitration with the necessary assistance of directing groups (Scheme 1, Route B);⁷ (2) nitration at the ortho- and para-position of phenol or amines (Scheme 1, Route C).⁸ Although these nitration methods have gained significant developments, the direct nitration of heterocycles has rarely been reported.

Scheme 1 Direct C–H nitration of olefins and arenes.

Quinoline N-oxides and quinoline derivatives exist widely in natural products, pharmaceuticals and functional materials. Generally, quinoline N-oxides⁹ were used as a typical substrate to realize C-2 functionalization via C–H bond activation.¹⁰ Meanwhile, the nitration of quinoline N-oxides usually proceed at the 4 or 8-position in the presence of mixed acid (Scheme 2).^11,12 Comparing with the above mentioned C2- and C4-functionalization of quinoline N-oxide, the direct C3-functionalization including the nitration has rarely been achieved. Considering that the electron density of C3 position is slightly higher than that of C2 and C4 sites, it is speculated to provide a way to develop selective C3-functionalization method through electrophilic radical coupling strategy. As part of our continuing interest in free radical and the heterocyclic chemistry,¹³ we herein disclose our investigation on the direct C3 nitration of quinoline N-oxide using TBN as an eco-friendly nitration source under metal free conditions. Although it is known that the selectivity of free-radical transformation is difficult to control, our methodology displays excellent C3 selectivity and can be smoothly scaled up.

Scheme 2 The nitration of quinoline N-oxides at different positions.

Quinoline N-oxide 1a was initially chosen as the model substrate to screen the various reaction parameters (Table 1). The 3-nitroquinoline N-oxide 2a was isolated in 50% yield using NaNO₂ as NO₂ source with the assistance of Pd(OAc)₂ and K₂S₂O₈ in MeCN (entry 1). However, only trace amount of 2a was observed in the absence of Pd(OAc)₂ (entry 2). Surprisingly, when TBN was employed as the nitro source and oxidant, the desired 2a was obtained in 77% yield (entry 3). Running the reaction under oxygen or argon atmosphere made the yield decrease to 53% and 66%, respectively (entries 4 and 5). The reaction proceeded smoothly in DCE and toluene (entries 6 and 7). Unfortunately, the reaction did not work in H₂O (entry 8). To be noteworthy, 94% yield could be obtained when the loading of TBN was increased to 3.5 equivalent (entry 10). In addition, decreasing the temperature brought a distinct decrease in the yields (entries 11–13), implying such reaction is quite sensitive to temperature variation.

Table 1 Optimization of reaction conditions^a

Entry	NO2 source (equiv.)	Solvent	T (°C)	Yield (%)
a All reactions were carried out on a 0.3 mmol scale in 3 mL of solvent for 24 h. Isolated yield.b K2S2O8 (2.5 equiv.) was added.c Pd(OAc)2 (10 mmol%) was added.d Under oxygen in pressure tubes.e Under argon in pressure tubes.
1^b^,^c	NaNO2 (2.5)	MeCN	100	50
2^b	NaNO2 (2.5)	MeCN	100	Trace
3	t-BuONO (2.5)	MeCN	100	77
4^d	t-BuONO (2.5)	MeCN	100	53
5^e	t-BuONO (2.5)	MeCN	100	66
6	t-BuONO (2.5)	DCE	100	74
7	t-BuONO (2.5)	Toluene	100	72
8	t-BuONO (2.5)	H2O	100	N.R.
9	t-BuONO (3.0)	MeCN	100	89
10	t-BuONO (3.5)	MeCN	100	94
11	t-BuONO (3.5)	MeCN	80	74
12	t-BuONO (3.5)	MeCN	50	28
13	t-BuONO (3.5)	MeCN	25	N.R.

---

With these satisfactory conditions in hand, we then turned to examining the scope of quinoline N-oxides for this transformation (Table 2). Quinoline N-oxides containing electron-donating groups (OMe, Me, Ph) and electron-withdrawing groups (Br, Cl) at the 5, 6, 7, 8-positions all underwent nitration smoothly at the 3-position. 5-Bromo, 5-methoxy and 5-phenyl quinoline N-oxides gave the desired products (2b–2d) in 60–75% yields, respectively. Likewise, 6-substitued quinoline N-oxides yielded 60–82% products (2e–2i). Meanwhile, 7-methyl quinoline N-oxide afforded 2j in 64% yield. Besides, 8-substituted quinoline N-oxides still gave the desired products (2k and 2l) in moderate yields. Unfortunately, the 2,4-substituted quinoline N-oxides were not suitable for this transformation.¹⁴ No products were afforded when isoquinoline N-oxide and pyridine N-oxide were utilized as the substrates. The structure of the nitroquinoline N-oxide 2j was further confirmed by X-ray crystallography (XRD) (CCDC 1031244).

Table 2 Direct C3 nitration of different quinoline N-oxides^a

a A mixture of quinoline N-oxides (0.3 mmol), t-BuONO (1.05 mmol), in 3 mL of MeCN was stirred in 15 mL pressure tubes at 100 °C for 24 h. Isolated yields.b DCM instead of MeCN owing to poor solubility of 1i.

---

In order to prove the practicality of this approach, a gram-scale synthesis of the 3-nitroquinoline N-oxides 2a (1.36 g, 72% yield) was performed, which suggested that such methodology could also be efficiently scaled up (Scheme 3).

Scheme 3 Gram scale synthesis of 2a.

Furthermore, 3-nitroquinoline N-oxides 2a could be selectively reduced by PCl₃ to give the corresponding 3-nitroquinoline 3a in 92% yield. Compound 2a could be hydrogenated to 3-aminoquinoline 3b in 74% yield using Pd²@NAC-800 catalyst¹⁵ under 1 atm H₂ at room temperature (Scheme 4).

Scheme 4 Transformations of 3-nitroquinoline N-oxide.

In order to deeply understand the mechanism, a series of control experiments were carried out (Scheme 5). The addition of either TEMPO (2,2,6,6-tetramethylpiperidinooxy) or BHT (2,6-di-tert-butyl-4-methylphenol) could stop such nitration reaction (Scheme 5, eqn (a) and (b)). The reaction was also inhibited by 1,1-diphenylethylene, and 1,1-diphenyl-2-nitroethylene was isolated in 55% yield (Scheme 5, eqn (c)).^6b These results may suggest that the reaction undergo a free radical process and NO₂ radical was involved in present transformation. After the reaction, tertiary butanol was detected by GC-MS, which showed that t-BuONO may generate ^tBuO radical and NO radical, and the latter could be easily oxidized to NO₂ radical via a SET process.¹⁶

Scheme 5 Radical trapping experiments.

Based on the above control experiments, a plausible mechanism was proposed as shown in Scheme 6. Initially, TBN generates NO radical, which could be oxidized to NO₂ radical via a SET process.^5c,16 Then the NO₂ radical and quinoline N-oxides generated radical A through an electrophilic radical addition process. Eventually, the desired product was generated via a single-electron oxidation process with the assistance of NO₂ or ^tBuO radical.

Scheme 6 Plausible reaction mechanism.

In summary, we have successfully developed a direct and eco-friendly methodology for the regioselective synthesis of 3-nitroquinoline N-oxides in the absence of any metal catalyst and external oxidant. This transformation is realized due to the higher electron density of C3 position and the electrophilic property of NO₂ radical. Furthermore, it is worth noting that such transformation could also be smoothly scaled up. The reactions of free radicals with other coupling partners are under investigation in our laboratory.

Acknowledgements

We gratefully acknowledge the Chinese Academy of Sciences and the National Natural Science Foundation of China (21133011 and 21373246) and the “Strategic Priority Research Program” of the Chinese Academy of Sciences (XDA09030104) for generous financial support.

Notes and references

1. For an excellent review on aromatic nitro compounds, see: G. Yan and M. Yang, Org. Biomol. Chem., 2013, 11, 2554.
2. (a) N. Ono, The Nitro Group in Organic Synthesis, Wiley-VCH, 2001; (b) K. Schofield, Aromatic Nitrations, Cambridge University Press, Cambridge, 1980; (c) H. Feuer and A. T. Nielson, Nitro Compounds: Recent Advances in Synthesis and Chemistry, VCH, Weinheim, 1990; (d) G. A. Olah, R. Malhotra and S. C. Narang, Nitration: Methods and Mechanisms, VCH, Weinheim, 1989.
3. For selected reports on nitrate salts as the nitro source, see: (a) S. Manna, S. Maity, S. Rana, S. Agasti and D. Maiti, Org. Lett., 2012, 14, 1736; (b) N. Nowrouzi, A. M. Mehranpour, E. Bashiri and Z. Shayan, Tetrahedron Lett., 2012, 53, 4841; (c) M. A. Zolfigol, A. Khazaei, A. R. Moosavi-Zare, A. Zare, H. G. Kruger, Z. Asgari, V. Khakyzadeh and M. Kazem-Rostami, J. Org. Chem., 2012, 77, 3640; (d) J. Jacoway, G. G. K. S. N. Kumar and K. K. Laali, Tetrahedron Lett., 2012, 53, 6782.
4. For selected reports on nitrite salts as the nitro source, see: (a) Y.-M. Li, X.-H. Wei, X.-A. Li and S.-D. Yang, Chem. Commun., 2013, 49, 11701; (b) B. P. Fors and S. L. Buchwald, J. Am. Chem. Soc., 2009, 131, 12898; (c) P. J. A. Joseph, S. Priyadarshini, M. L. Kantam and H. Maheswaran, Tetrahedron Lett., 2012, 53, 1511; (d) G. Yan, L. Zhang and J. Yu, Lett. Org. Chem., 2012, 9, 133; (e) H. J. Yang, Y. Li, M. Jiang, J. M. Wang and H. Fu, Chem.–Eur. J., 2011, 17, 5652.
5. (a) X. Wu, J. Schranck, H. Neumann and M. Beller, Chem. Commun., 2011, 47, 12462; (b) X. Wu, H. Neumann and M. Beller, Chem. Commun., 2011, 47, 7959; (c) T. Shen, Y. Yuan and N. Jiao, Chem. Commun., 2014, 50, 554; (d) S. Wang, C. Shu, T. Wang, J. Yu and G. Yan, Chin. Chem. Lett., 2012, 23, 643.
6. (a) S. Maity, S. Manna, S. Rana, N. Togati, A. Mallick and D. Maiti, J. Am. Chem. Soc., 2013, 135, 3355; (b) S. Maity, N. Togati, U. Sharma and D. Maiti, Org. Lett., 2013, 15, 3384; (c) S. Manna, S. Jana, T. Saboo, A. Maji and D. Maiti, Chem. Commun., 2013, 49, 5286; (d) N. Togati, S. Maity, U. Sharma and D. Maiti, J. Org. Chem., 2013, 78, 5949; (e) I. Jovel, S. Prateeptongkum, R. Jackstell, N. Vogl, C. Weckbecker and M. Beller, Adv. Synth. Catal., 2008, 350, 2493.
7. (a) Y.-F. Liang, X. Li, X. Wang, Y. Yan, P. Feng and N. Jiao, ACS Catal., 2015, 5, 1956; (b) F. Xie, Z. Qi and X. Li, Angew. Chem., Int. Ed., 2013, 52, 11862; (c) L. Zhang, Z. Liu, H. Li, G. Fang, B.-D. Barry, T. A. Belay, X. Bi and Q. Liu, Org. Lett., 2011, 13, 6536; (d) Y.-K. Liu, S.-J. Lou, D.-Q. Xu and Z.-Y. Xu, Chem.–Eur. J., 2010, 16, 13590; (e) D. Katayev, K. F. Pfister, T. Wendling and L. J. Gooßen, Chem.–Eur. J., 2014, 20, 9902; (f) B. Majhi, D. Kundu, S. Ahammed and B. C. Ranu, Chem.–Eur. J., 2014, 20, 9862; (g) W. Zhang, S. Lou, Y. Liu and Z. Xu, J. Org. Chem., 2013, 78, 5932; (h) P. Sadhu, S. K. Alla and T. Punniyamurthy, J. Org. Chem., 2014, 79, 8541.
8. (a) Y.-X. Li, L.-H. Li, Y.-F. Yang, H.-L. Hua, X.-B. Yan, L.-B. Zhao, J.-B. Zhang, F.-J. Ji and Y.-M. Liang, Chem. Commun., 2014, 50, 9936; (b) D. Koley, O. C. Colón and S. N. Savinov, Org. Lett., 2009, 11, 4172; (c) B. Kilpatrick, M. Heller and S. Arns, Chem. Commun., 2013, 49, 514; (d) A. K. Bose, S. N. Ganguly, M. S. Manhas, S. Rao, J. Speck, U. Pekelny and E. Pombo-Villars, Tetrahedron Lett., 2006, 47, 1885.
9. The quinoline N-oxides were easily prepared from quinoline with m-CPBA, see: G. Li, C. Jia and K. Sun, Org. Lett., 2013, 15, 5198.
10. (a) G. Yan and M. Yang, Adv. Synth. Catal., 2014, 356, 2375; (b) J. Wu, X. Cui, L. Chen, G. Jiang and Y. Wu, J. Am. Chem. Soc., 2009, 131, 13888; (c) X. Chen, C. Zhu, X. Cui and Y. Wu, Chem. Commun., 2013, 49, 6900; (d) Z. Wu, C. Pi, X. Cui, J. Bai and Y. Wu, Adv. Synth. Catal., 2013, 355, 1971; (e) G. Li, C. Jia and K. Sun, Org. Lett., 2013, 15, 5198; (f) S. H. Cho, S. J. Hwang and S. Chang, J. Am. Chem. Soc., 2008, 130, 9254; (g) X. Gong, G.-Y. Song, H. Zhang and X.-W. Li, Org. Lett., 2011, 13, 1766; (h) Y. Shen, J. Chen, M. Liu, J. Ding, W. Gao, X. Huang and H. Wu, Chem. Commun., 2014, 50, 4292; (i) Z. Wu, H. Song, X. Cui, C. Pi, W. Du and Y. Wu, Org. Lett., 2013, 15, 1270.
11. (a) T. Kaiya, N. Shirai and Y. Kawazoe, Chem. Pharm. Bull., 1986, 34, 881; (b) L. H. Heitman, A. Goblyos, A. M. Zweemer, R. Bakker, T. Mulder-Krieger, J. P. D. Veldhoven, H. Veies, J. Brussee and A. P. IJzerman, J. Med. Chem., 2009, 52, 926.
12. Only one example of 3-nitroquinoline N-oxides was reported, using stoichiometric AgNO₃ as the nitrating agent, but only in 33% yield, see: K. S. Sharma, S. Kumari and R. P. Singh, Synthesis, 1981, 316.
13. (a) J. Zhao, P. Li, C. Xia and F. Li, Chem. Commun., 2014, 50, 4751; (b) P. Li, J. Zhao, C. Xia and F. Li, Org. Lett., 2014, 16, 5992; (c) P. Li, J. Zhao, R. Lang, C. Xia and F. Li, Tetrahedron Lett., 2014, 55, 390; (d) Q. Xing, P. Li, H. Lv, R. Lang, C. Xia and F. Li, Chem. Commun., 2014, 50, 12181.
14. Possibly owing to the steric effect of 2 or 4-position, quinoline N-oxide derivatives (such as 2-Cl, 2-Me, 4-Me, 4-NO₂) were not suitable for this transformation.
15. The synthesis of Pd²@NAC-800, see: Z. Li, J. Li, J. Liu, Z. Zhao, C. Xia and F. Li, ChemCatChem, 2014, 6, 1333.
16. The NO radical was easily oxidized to NO₂ radical in the presence of trace amount of O₂ and H₂O, see: (a) T. Taniguchi, A. Yajima and H. Ishibashi, Adv. Synth. Catal., 2011, 353, 2643; (b) I. Jovel, S. Prateeptongkum, R. Jackstell, N. Vogl, C. Weckbecker and M. Beller, Adv. Synth. Catal., 2008, 350, 2493.

---

Footnote

† Electronic supplementary information (ESI) available. CCDC 1031244. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra04632g

---