Page 3 of 5
Organic & Biomolecular Chemistry
DOI: 10.1039/C5OB01900A
COMMUNICATION
analysis of the residual material mixture. The data indicate that
cleavage of the heteroaryl C–H bond is not the rateꢀdetermining
step.
[2] a) G. Rouquet, N. Chatani, Chem. Sci 2013, 4, 2201ꢀ2208; b) B. Xiao, Z. J.
Liu, L. Liu, Y. Fu, J. Am. Chem. Soc. 2013, 135, 616–619; c) T. J. Gong, B.
Xiao, W. M. Cheng, W. Su, J. Xu, Z. J. Liu, L. Liu, Y. Fu, J. Am. Chem. Soc.
2013, 135, 10630–10633; d) Z. Wang, Y. Kuninobu, M. Kanai, J. Am.
Chem. Soc. 2015, 137, 6140–6143; e) J. R. Hummel, J. A. Ellman, J. Am.
Chem. Soc. 2015, 137, 490–498; f) W. J. Han, G. Y. Zhang, G. X. Li, H. M.
Huang, Org. Lett. 2014, 16, 3532–3535; g) B. Du, B. Jin, P. P. Sun, Org.
Lett 2014, 16, 3032–3035; h) Z. Z. Yu, B. Ma, M. J. Chen, H. H. Wu, L. Liu,
J. L. Zhang, J. Am. Chem. Soc 2014, 136, 6904–6907; l) J. X. Yan, H. Li, X.
W. Liu, J. L. Shi, X. Wang, Z. J. Shi, Angew. Chem. Int. Ed 2014, 53,
4945–4949.
A possible mechanism is proposed (Scheme 4) based on our
findings
and
previous
studies[9–13]
.
Initially,
thermal
decomposition of DCP generates 2 equiv. of 2ꢀphenylpropanoxy
radical (Scheme 4, A), which gives the methyl radical (Scheme
4, B) by the loss of 2ꢀphenylpropanꢀ2ꢀol molecule. The methyl
radical then attacks Nꢀoxide to form an active radical species
(Scheme 4, C). With assistance of DCP, radical species C
yields the desired methylation product, 2ꢀphenylpropanꢀ2ꢀol, and
the radical species
A
via single electron transfer. 2ꢀ
[3] a) C. H. Bai, X. F. Yao, Y. W. Li, ACS Catal. 2015, 5, 884–891; b) V.
Bagchi, P. Paraskevopoulou, P. Das, L. Y. Chi, Q. W. Wang, A. Choudhury,
J. S. Mathieson, L. Cronin, D. B. Pardue, T. R. Cundari, G. Mitrikas, Y.
Sanakis, P. Stavropoulos, J. Am. Chem. Soc. 2014, 136, 11362–11381; c)
C. W. Zhu, M. L. Yi, D. H. Wei, X. Chen, Y. J. Wu, X. L. Cui, Org. Lett.
2014, 16, 1840–1843; d) D. G. Yu, M. Suri, F. Glorius, J. Am. Chem. Soc.
2013, 135, 8802–8805;e) L. S. Wang, Z. J. Shi, Nat. Commun. 2014, 5,
4707–4712; f) H. Q. Zhao, M. Wang, W. P. Su, M. C. Hong, Adv. Synth.
Catal. 2010, 352, 1301–1306.
Phenylpropanꢀ2ꢀol loses a H2O molecule to produce 2ꢀphenylꢀ1ꢀ
propene. Moreover, radical species A initiates a new reaction
cycle.
Scheme 4. Propose mechanism of the methylation.
O
Ph
CH3
Ph
CH3
Ph
O
O
2
O
CH3
Ph
B
A
[4] a) L. Ju, J. Z. Yao, Z. H. Wu, Z. X. Liu, Y. H. Zhang, J. Org. Chem. 2013,
78, 10821–10831; b) S. Luo, F. X. Luo, X. S. Zhang, Z. J. Shi, Angew.
Chem. Int. Ed 2013, 58, 10598–10601.
O
N
Ph
CH3
ꢀ
O
Ph
OH
+
[5] a) D. Das, D. Seidel, Org. Lett. 2013, 15, 4358–4361; b) B. Xiao, T. J.
Gong, Z. J. Liu, J. H. Liu, D. F. Luo, J. Xu, L. Liu, J. Am. Chem. Soc. 2011,
133, 9250–9253; c) S. Wang, R. Guo, G. Wang, S. Y. Chen, X. Qi. Yu,
Chem. Commun 2014, 50, 12718–12721.
ꢀH2O
N
+
Ph
CH3
ꢀ
O
+
H
CH3
O
N
O
[6] a) D. Zhang, X. L. Cui, Q. Q. Zhang, Y. J. Wu, J. Org. Chem 2015, 80,
1517–1522; b) F. J. Chen, G. Liao, X. Li, J. Wu, B. F. Shi, Org. Lett 2014,
16, 5644–5647; c) V. P. Reddy, R. H. Qiu, T. Iwasaki, N. Kambe, Org.
Biomol. Chem 2015, 13, 6803ꢀ6813.
Ph
C
In summary, we have developed a method to achieve metalꢀ
free methylation of pyridine Nꢀoxide using peroxides as
methylation reagents. Metalꢀfree methylation is a practical and
convenient method to introduce methyl groups into a pyridine
ring. Further investigations of applications in synthesis chemistry
and expansion of the substrate scope using peroxides as
methylation reagents are underway in our laboratory.
[7] a) S. Y. Zhang, G. He, W. A. Nack, Y. S. Zhao, Q. Li, G. Chen, J. Am.
Chem. Soc. 2013, 135, 2124−2127; b) S. Y. Zhang, Q. Li, G. He, W. A.
Nack, G. Chen, J. Am. Chem. Soc. 2013, 135, 12135−12141; c) R. Y. Zhu,
J. He, X. C. Wang, J. Q. Yu, J. Am. Chem. Soc. 2014, 136, 13194ꢀ13197;
d) X. C. Wang, W. Gong, L. Z. Fang, R. Y. Zhu, S. Li, K. M. Engle, J. Q.
Yu, Nature 2015, 519, 334−338.
[8] a) H. Wang, S. J. Yu, Z. S. Qi, X. W. Li, Org. Lett. 2015, 17, 2812–2815; b)
T. Kobayakawa, T. Narumi, H. Tamamura, Org. Lett. 2015, 17, 2302–
2305; c) S. Darses, J. P. Genet, Chem. Rev. 2008, 108, 288−325; d) S. R.
Neufeldt, C. K. Seigerman, M. S. Sanford, Org. Lett. 2013, 15,
2302−2305; e) J. C. Tellis, D. N. Primer, G. A. Molander, Science 2014,
345, 433−436; f) D. N. Primer, I. Karakaya, J. C. Tellis, G. A. Molander, J.
Am. Chem. Soc. 2015, 137, 2195−2198. g) J. Wippich, I. Schnapperelle,
T. Bach, Chem. Commun. 2015, 51, 3166−3168.
Experimental Section
Typical Procedure for the Methylation of Pyridine N-Oxides: Pyridine-N-oxide
(0.5 mmol) and DCP (1 mmol, 1 equiv.) were charged into a 30 mL pressure
tube sealed with rubber plugs. The reaction mixture was stirred at 120 °C for 24
h under a N2 atmosphere. After the starting material was completely consumed
[based on thin layer chromatography (TLC) monitoring with EtOAc:methanol as
the eluent], the reaction was cooled to room temperature. The mixture was
purified by column chromatography on silica gel (200–300 mesh) to afford the
desired products.
[9] Y. H. Zhang, J. Q. Feng, C. J. Li, J. Am. Chem. Soc. 2008, 130, 2900−
2901.
[10] a) Q. Q. Xia, X. L. Liu, Y. J. Zhang, C. Chen, W. Z. Chen, Org. Lett. 2013,
15, 3326–3329; b)Y. Zhu, H. Yan, L. H. Lu, D. F. Liu, G. W. Rong, J. C.
Mao, J. Org. Chem. 2013, 78, 9898−9905.
[11] S. J. Guo, Q. Wang, Y. Jiang, J. T. Yu, J. Org. Chem. 2014, 79,
11285−11289.
Acknowledgement
[12] a) Z. B. Xu, C. X. Yan, Z. Q. Liu,Org. Lett. 2014, 16, 5670−5673; b) J. H.
Fan, M. B. Zhou, Y. Liu, W. T. Wei, X. H. Ouyang, R. J. Song, J. H. Li,
Synlett 2014, 25, 0657–0660; c) Q. Dai, J. T. Yu, Y. Jiang, S. J. Guo, H. T.
Yang, J. Cheng, Chem. Commun 2014, 50, 3865−3867.
We gratefully acknowledge the financial support from the National
Natural Science Foundation of China (NSFC, No. 21102005).
Keywords: Alkylation • C–H activation • Nitrogen heterocycles •
[13] Y. J. Bao, Y. Z. Yan, K. Xu, J. H. Su, Z. G. Zha, Z. Y. Wang, J. Org. Chem
2015, 80, 4736−4742.
Nitrogen oxides • Radical reactions
[14] D. A. DiRocco, K. Dykstra, S. Krska, P. Vachal, D. V. Conway, M. Tudg,
Angew. Chem. Int. Ed, 2014, 53, 4802–4806.
[1] For recent selected reviews on CꢀH bond functionalization, see: a) J. Q. Yu,
Z. J. Shi, CꢀH Activation; SpringerꢀVerlag: Berlin Heidelberg, 2010; b) T.
Bruckl, R. D. Baxter, Y. Ishihara, P. S. Baran, Acc. Chem. Res. 2012, 45,
826–839; c) P. B. Arockiam, C. Bruneau, P. H. Dixneuf, Chem. Rev. 2012,
112, 5879ꢀ5918; d) C. L. Sun, B. J. Li, Z. J. Shi, Chem. Rev. 2011, 111,
1293–1314. e) T. W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110, 1147–
1169.
[15] J. Jin, D. W. C. MacMillan, Nature, 2015, 525, 87–90.
[16] J. Gui, Q. Zhou, C.ꢀM.Pan, Y. Yabe, A. C.Burns, M. R.Collins, M.
A.Ornelas, Y. Ishihara, P. S. Baran, J. Am. Chem. Soc. 2014, 136,
4853– 4856.