Copper-mediated C(sp³)–H amination in a multiple C–N bond-forming strategy for the synthesis of N-heterocycles

Abstract

An efficient construction of imidazo[1,5-a]pyridines, through a three-component reaction involving benzyl substituted pyridines, aldehydes, and TMSN₃, has been developed. Three C–N bonds were formed in one pot. Copper-promoted amination of the benzylic C(sp³)–H bond is a key step of this multiple C–N bond-forming sequence.

---

Carbon–nitrogen bond formation is one of the major topics of organic synthesis due to the great importance of nitrogen-containing compounds in natural products, pharmaceuticals, and agrochemicals as well as functional chemicals.¹ In recent years, transition-metal-catalyzed amination/amidation of C–H bonds has emerged as an atom-economical and efficient alternative to traditional C–N bond-forming methods using prefunctionalized substrates.^2–4 Organic azides have been utilized increasingly as amino sources recently, since the method normally requires no extra oxidant and only N₂ gas is released as a by-product.⁵ Additionally, structurally diversified organic azides are readily available. As a result, a variety of transition-metal-based catalytic systems have successfully been exploited in directed intermolecular C–H amination/amidation with organic azides.^6–11 Although great success has been achieved in this field, some challenges still exist: (1) a process involving multiple C–N bond formation is uncommon; (2) the use of a directing group limits the application of this strategy; (3) intermolecular amidation/amination of the C(sp³)–H bond is still rare.¹² Recently, a cascade intermolecular C(sp²)–H amidation and intramolecular N–N bond-forming strategy using organic azides was applied in the synthesis of indazoles.^13,14 Herein, we report a new synthesis of imidazo[1,5-a]pyridines via amination of a sp³ hybridized C–H bond as a key C–N bond-forming step with TMSN₃ as an amino source promoted by Cu(II) (Scheme 1). In this three-component reaction involving benzyl substituted N-heterocycles, aldehydes, and TMSN₃, imidazo[1,5-a]pyridines and related more complicated fused heterocycles were constructed with sequential three C–N bonds formation. Besides, the heterocyclic nitrogen acted as both a directing group and an intramolecular nucleophile in this process.

Scheme 1 C–H amination/amidation for the construction of N-heterocycles.

The scaffold of imidazo[1,5-a]pyridine¹⁵ exists in many natural products and pharmaceutical agents with broad biological activities, such as antimicrobial, anti-neoplastic, anti-anxiety, and anti-inflammatory and consequently, much attention has been paid to its synthesis. Methods for the synthesis of imidazo[1,5-a]pyridines are mainly limited to 1,2,3-triazolo[1,5-a]pyridine-derived carbene insertion into nitriles, and Vilsmeier-type dehydrative cyclization of N-2-pyridylmethylamides and oxidative cyclization of 2-pyridinyl imine or amine derivatives.¹⁶ However, most of the starting materials applied in these methods require multiple-step preparations. The general procedure reported here starts from readily available substrates with C(sp³)–H amination as a key step.

We initiated the study with a reaction between 2-benzylpyridine 1a, p-chlorobenzaldehyde 2a, and TMSN₃ under the reaction conditions we reported recently.^10a The desired product, 3-(4-chlorophenyl)-1-phenylimidazo[1,5-a]pyridine 3a, was isolated in 14% yield. Then, different acids in place of PivOH were tested. PivOH was proved to be the additive of choice (entries 1–5, Table 1). DCB (o-dichlorobenzene) was a better solvent than the others screened (entries 6–8). Investigation of copper salts indicated that Cu(TFA)₂·H₂O was optimal. When the reaction was subjected to a catalytic amount of Cu(TFA)₂·H₂O (0.2 equiv.) with oxidants such as TBHP and dioxygen, the corresponding oxidation by-product, phenyl(pyridin-2-yl)methanone, was obtained and only a trace amount of the desired product 3a was detected. During the optimization, we found that 2-benzylpyridine was partially oxidized to the corresponding ketone. The yield of 3a was improved to 28% when the amount of 1a was doubled (entry 11). Addition of TMSN₃ in two portions and increasing the loading of Cu(TFA)₂ to 1.2 equiv. were helpful for product formation (entries 12 and 13). Finally, the yield was maximized to 72% when the reaction was performed in a higher concentration and a total of 4.0 equivalents of TMSN₃ (3 + 1) were applied (entries 14 and 15).

Table 1 Optimization of the reaction conditions^a

Entry	Copper (equiv.)	Additive (1 equiv.)	Solvent (mL)	Yield (%)
a Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), copper salt, additive (1.0 equiv.), TMSN3 (3.0 equiv.), solvent, in Ar, 110 °C. b 1a (0.4 mmol) and 2a (0.2 mmol). c Addition of TMSN3 (2.0 equiv.) at the beginning of the reaction, and the second portion of TMSN3 (1.0 equiv.) was added after 8 h. d Addition of TMSN3 (3.0 equiv.) at the beginning of the reaction, and the second portion of TMSN3 (1.0 equiv.) was added after 8 h. DCB = o-dichlorobenzene, PivOH = pivalic acid, TFA = trifluoroacetic acid, TsOH = p-toluenesulfonic acid, and HOTf = trifluoromethanesulfonic acid.
1	Cu(TFA)2 (1.0)	PivOH	DCB (2)	14
2	Cu(TFA)2 (1.0)	TFA	DCB (2)	n.d.
3	Cu(TFA)2 (1.0)	TsOH	DCB (2)	Trace
4	Cu(TFA)2 (1.0)	HOTf	DCB (2)	n.d.
5	Cu(TFA)2 (1.0)	—	DCB (2)	10
6	Cu(TFA)2 (1.0)	PivOH	Toluene (2)	Trace
7	Cu(TFA)2 (1.0)	PivOH	DMF (2)	Trace
8	Cu(TFA)2 (1.0)	PivOH	DCE (2)	Trace
9	Cu(OAc)2 (1.0)	PivOH	DCB (2)	<5
10	CuCl2 (1.0)	PivOH	DCB (2)	<5
11^b	Cu(TFA)2 (1.0)	PivOH	DCB (2)	28
12^b^,^c	Cu(TFA)2 (1.0)	PivOH	DCB (2)	32
13^b^,^c	Cu(TFA)2 (1.2)	PivOH	DCB (2)	47
14^b^,^c	Cu(TFA)2 (1.2)	PivOH	DCB (0.3)	60
15 ^,	Cu(TFA) 2 (1.2)	PivOH	DCB (0.3)	72

---

With the optimal conditions in hand, we started to examine the generality of aldehydes applicable to this three-component reaction (Scheme 2). Benzaldehydes substituted at the para position with either electron-donating OMe, Me or electron-withdrawing NO₂ groups reacted smoothly with 1a and TMSN₃ to give the corresponding products in 62% to 69% yield (3c–3e), demonstrating that the electronic density of the aromatic aldehydes had little effect on the product formation. Benzaldehydes bearing ortho substituents (Me, F) also gave the desired products (3f, 3g) in comparable yields. Furthermore, thiophene-2-carbaldehyde and furyl aldehyde afforded the corresponding heterocycle substituted products (3i, 3j) in 83% and 53% yield, respectively. Unfortunately, the aliphatic aldehydes failed to deliver the corresponding products with the method. It was notable that in these cases, no by-product, derived from either the Schmidt reaction¹⁷ or Jiao's reaction¹⁸ through C–C bond cleavage, was detected.

Scheme 2 The scope of aldehydes. Reaction conditions: 1a (0.4 mmol, 2.0 equiv.), 2 (0.2 mmol, 1.0 equiv.), PivOH (0.2 mmol, 1.0 equiv.), Cu(TFA)₂·H₂O (0.24 mmol, 1.2 equiv.), DCB (0.3 mL), TMSN₃ (0.6 mmol, 3.0 equiv., 8 h, then 0.2 mmol, 1.0 equiv., 8 h), 110 °C, in Ar.

Then, the scope of substituents on the phenyl ring of 2-benzylpyridine was studied (Scheme 3). Electron-rich 2-benzylpyridines afforded the corresponding products in higher yields than those substituted with electron-withdrawing CF₃ or F groups in reactions with p-chlorobenzaldehyde 2a (3m and 3nvs. 3k and 3l). Besides pyridine, other N-heterocycles could also be used to build fused heterocyclic systems. For example, 2-benzylbenzothiazole and 2-benzylbenzoxazole reacted smoothly with 2a to afford the more complicated tricyclic scaffolds 3o and 3p in good yields. Isoquinoline is an excellent directing group in this highly efficient C–N bond-forming reaction, delivering 3q in 90% yield. Substituted imidazo[1,5-a]pyrimidine derivative 3r could also be obtained in 60% yield by applying this method.

Scheme 3 The scope of N-heterocycles. Reaction conditions: 1 (0.4 mmol, 2.0 equiv.), 2a (0.2 mmol, 1.0 equiv.), PivOH (0.2 mmol, 1.0 equiv.), Cu(TFA)₂·H₂O (0.24 mmol, 1.2 equiv.), DCB (0.3 mL), TMSN₃ (0.6 mmol, 3.0 equiv., 8 h, then 0.2 mmol, 1.0 equiv., 8 h), 110 °C, in Ar.

In order to gain insights into the reaction mechanism, some possible reaction intermediates derived from benzaldehyde, such as benzonitrile, benzoic acid and benzamide, reacted with 1a and TMN₃ under the standard conditions. No trace amount of the desired product was detected in these cases. Phenyl(pyridin-2-yl)methanone, the oxidation by-product of 1a, also failed to give 3a in a reaction with 2a and TMSN₃. Then, azidation or amination of one of the benzylic C–H bonds was proposed as the initial step of this multiple C–N forming sequence. Therefore, the corresponding amino and azido substituted derivatives 4 and 5 were synthesized and tested (Scheme 4). Both 4 and 5 could react with 2a in the absence of TMSN₃ to give the desired product 3a in 95% and 16% yield, respectively. However, the amino intermediate was not detected even in the absence of an aldehyde, probably due to its instability under the reaction conditions. We proposed that amination of the C(sp³)–H bond in 1a rather than azidation was likely the first step triggering the following processes.

Scheme 4 Reactions of possible intermediates.

Although the exact mechanism of this reaction is not completely clear at this stage, a plausible mechanism was proposed (Scheme 5).^10a,12b Initially, coordination of Cu(II) with the pyridinyl nitrogen facilitates the deprotonation by the pivaloate anion to give intermediate A. Subsequently, the azido anion derived from HOPiv and TMSN₃ may replace TFA in A to form intermediate B. The carbon–copper bond may be formed in intermediate Cvia 1,3-migration. With the assistance of acids, the first C–N bond was formed with the release of N₂ as a driving force, delivering the aminated intermediate 5via intermediates D and E.¹⁹ Then, condensation of 5 with aldehydes followed by cycloaddition generates intermediate G. Finally, oxidative aromatization by Cu(II) gives the desired product 3.^16d

Scheme 5 Proposed mechanism.

Conclusions

In conclusion, we have developed an efficient method for the synthesis of fused heterocycles containing the imidazole moiety starting from benzyl substituted N-heterocycles and aldehydes using TMSN₃ as a nitrogen source. Copper-mediated amination of the sp³ hybridized C–H bond is the initial step for this multiple C–N bond-forming sequence. This methodology not only provides a useful approach for synthesis of imidazo[1,5-a]pyridines and related fused heterocycles, but also offers a new strategy for retro-synthetic analysis of certain N-heterocycles, in which multiple C–N bonds could be disconnected around aromatic nitrogen to yield simple and readily available feedstock chemicals as synthetic starting materials.

Acknowledgements

We are grateful for the financial support of the National Science Foundation of China (21272233, 21472190).

Notes and references

1. (a) R. Hili and A. K. Yudin, Nat. Chem. Biol., 2006, 2, 284; (b) Amino Group Chemistry: From Synthesis to the Life Sciences, ed. A. Ricci, Wiley-VCH, Weinheim, Germany, 2007; (c) P. A. Gale, Acc. Chem. Res., 2006, 39, 465.
2. (a) Metal-Catalyzed Cross-Coupling Reactions, ed. A. Meijere and F. Diederich, Wiley-VCH, Weinheim, 2004; (b) S. V. Ley and A. W. Thomas, Angew. Chem., Int. Ed., 2003, 42, 5400; (c) J. P. Corbet and G. Mignani, Chem. Rev., 2006, 106, 2651; (d) E. M. Beccalli, G. Broggini, M. Martinelli and S. Sottocornola, Chem. Rev., 2007, 107, 5318; (e) J. F. Hartwig, Acc. Chem. Res., 2008, 41, 1534; (f) F. Monnier and M. Taillefer, Angew. Chem., Int. Ed., 2008, 47, 3096; (g) D. S. Surry and S. L. Buchwald, Angew. Chem., Int. Ed., 2008, 47, 6338; (h) F. Monnier and M. Taillefer, Angew. Chem., Int. Ed., 2009, 48, 6954.
3. (a) S. H. Cho, J. Y. Kim, J. Kwak and S. Chang, Chem. Soc. Rev., 2011, 40, 5068; (b) T. R. M. Rauws and B. U. W. Maes, Chem. Soc. Rev., 2012, 41, 2463; (c) Z. Shi, C. Zhang, C. Tang and N. Jiao, Chem. Soc. Rev., 2012, 41, 3381; (d) C. Zhang, C. Tang and N. Jiao, Chem. Soc. Rev., 2012, 41, 3464; (e) G. Song, F. Wang and X. Li, Chem. Soc. Rev., 2012, 41, 3651; (f) J. Bariwal and E. Van der Eycken, Chem. Soc. Rev., 2013, 42, 9283; (g) D. N. Zalatan and J. Du Bois, in Topics in Current Chemistry, ed. J. Q. Yu and Z. Shi, Springer, Berlin, 2010, vol. 292, pp. 347–378.
4. (a) M. L. Louillat and F. W. Patureau, Chem. Soc. Rev., 2014, 43, 901; (b) K. Takamatsu, K. Hirano, T. Satoh and M. Miura, Org. Lett., 2014, 16, 2892; (c) H. Xu, X. Qiao, S. Yang and Z. Shen, J. Org. Chem., 2014, 79, 4414; (d) I. Sokolovs, D. Lubriks and E. Suna, J. Am. Chem. Soc., 2014, 136, 6920; (e) J. Huang, T. Mao and Q. Zhu, Eur. J. Org. Chem., 2014, 2878; (f) C. Zhu, M. Yi, D. Wei, X. Chen, Y. Wu and X. Cui, Org. Lett., 2014, 16, 1840; (g) B. L. Tran, B. Li, M. Driess and J. F. Hartwig, J. Am. Chem. Soc., 2014, 136, 2555; (h) M. Shang, S. Sun, H. X. Dai and J. Q. Yu, J. Am. Chem. Soc., 2014, 136, 3354.
5. (a) S. Cenini, E. Gallo, A. Caselli, F. Ragaini, S. Fantauzi and C. Piangiolino, Coord. Chem. Rev., 2006, 250, 1234; (b) S. Brase, C. Gil, K. Knepper and V. Zimmerman, Angew. Chem., Int. Ed., 2005, 44, 5188; (c) S. Lang and J. A. Murphy, Chem. Soc. Rev., 2006, 35, 146; (d) K. Shin, H. Kim and S. Chang, Acc. Chem. Res., 2015, 48, 1040.
6. For selected Rh-catalyzed C–H amidation using organo azide: (a) J. Y. Kim, S. H. Park, J. Ryu, S. H. Cho, S. H. Kim and S. Chang, J. Am. Chem. Soc., 2012, 134, 9110; (b) J. Ryu, K. Shin, S. H. Park, J. Y. Kim and S. Chang, Angew. Chem., Int. Ed., 2012, 51, 9904; (c) K. Shin, Y. Baek and S. Chang, Angew. Chem., Int. Ed., 2013, 52, 8031; (d) J. Jeong, P. Patel, H. Hwang and S. Chang, Org. Lett., 2014, 16, 4598; (e) H. Hwang, J. Kim, J. Jeong and S. Chang, J. Am. Chem. Soc., 2014, 136, 10770.
7. For selected Ir-catalyzed C–H amidation using organo azides: (a) J. Kim, J. Kim and S. Chang, Chem. – Eur. J., 2013, 19, 7328; (b) V. S. Thirunavukkarasu, K. Raghuvanshi and L. Ackermann, Org. Lett., 2013, 15, 3286; (c) M. Bhanuchandra, M. R. Yadav, R. K. Rit, M. R. Kuram and A. K. Sahoo, Chem. Commun., 2013, 49, 5225; (d) M. R. Yadav, R. K. Rit and A. K. Sahoo, Org. Lett., 2013, 15, 1638; (e) Q. Z. Zheng, Y. F. Liang, C. Qin and N. Jiao, Chem. Commun., 2013, 49, 5654; (f) K. Shin, J. Ryu and S. Chang, Org. Lett., 2014, 16, 2022; (g) E. Brachet, T. Ghosh, I. Ghosh and B. Konig, Chem. Sci., 2015, 6, 987.
8. For selected Ru-catalyzed C–H amidation using organo azides: (a) J. Ryu, J. Kwak, K. Shin, D. Lee and S. Chang, J. Am. Chem. Soc., 2013, 135, 12861; (b) J. Kim and S. Chang, Angew. Chem., Int. Ed., 2014, 53, 2203; (c) T. Kang, Y. Kim, D. Kee, Z. Wang and S. Chang, J. Am. Chem. Soc., 2014, 136, 4141; (d) K. Shin and S. Chang, J. Org. Chem., 2014, 79, 12197; (e) H. Kim, J. Park, J. G. Kim and S. Chang, Org. Lett., 2014, 16, 5466.
9. For selected Co-catalyzed C–H amidation using organo azides: (a) B. Sun, T. Yoshino, S. Matsunaga and M. Kanai, Adv. Synth. Catal., 2014, 356, 1491; (b) B. Sun, T. Yoshino, S. Matsunaga and M. Kanai, Chem. Commun., 2015, 51, 4649.
10. For selected Cu-catalyzed C–H amination/amidation using organo azides: (a) J. Peng, M. Chen, Z. Xie, S. Luo and Q. Zhu, Org. Chem. Front., 2014, 1, 777; (b) R. R. Donthiri, V. Pappula, N. N. K. Reddy, D. Bairagi and S. Adimurthy, J. Org. Chem., 2014, 79, 11277; (c) Y. M. Badiei, A. Dinescu, X. Dai, R. M. Palomino, F. W. Heinemann, T. R. Cundari and T. Warren, Angew. Chem., Int. Ed., 2008, 47, 9961.
11. Z. Hu, S. Luo and Q. Zhu, Sci. China: Chem., 2015, 58, 1349.
12. For selected recent papers on sp³ C–H amidation: (a) X. Huang, Y. Wang, J. Lan and J. You, Angew. Chem., Int. Ed., 2015, 54, 9404; (b) H. M. L. Davies and J. R. Manning, Nature, 2008, 451, 417; (c) J. L. Roizen, M. E. Harvey and J. Du Bios, Acc. Chem. Res., 2012, 45, 911; (d) F. Collet, R. G. Dodd and P. Dauban, Chem. Commun., 2009, 5061; (e) J. L. Jeffrey and R. Sarpong, Chem. Sci., 2013, 4, 4092; (f) H. Wang, G. Tang and X. Li, Angew. Chem., Int. Ed., 2015, 54, 13049.
13. (a) D. G. Yu, M. Suri and F. Glorius, J. Am. Chem. Soc., 2013, 135, 8802; (b) J. Peng, Z. Xie, S. Luo and Q. Zhu, Org. Lett., 2014, 16, 4702.
14. Selected papers on C–H azidation for the synthesis of heterocycles: (a) Q. Z. Zheng, P. Feng, Y. F. Liang and N. Jiao, Org. Lett., 2013, 15, 4262; (b) F. Xie, Z. S. Qi and X. W. Li, Angew. Chem., Int. Ed., 2013, 52, 11862; (c) C. Tang and N. Jiao, J. Am. Chem. Soc., 2012, 134, 18924; (d) Y. Peng, W. Wan, G. Ma, W. Gao, H. Jiang, S. Zhu and J. Hao, Chem. Commun., 2014, 50, 5733; (e) M. Devulapally, S. Pradeep and P. Tharmalingam, J. Org. Chem., 2015, 80, 1644.
15. For selected recent biological applications, see: (a) B. W. Trotter, Bioorg. Med. Chem. Lett., 2011, 21, 2354; (b) A. Kamalaaa, G. Ramakrishna and P. S. Ramakrishna, Eur. J. Med. Chem., 2011, 46, 2427; (c) G. R. Pettit, J. C. Collins, J. C. Knight, D. L. Herald, R. A. Nieman, M. D. Williams and R. K. Pettit, J. Nat. Prod., 2003, 66, 544; (d) A. A. Kalinin, A. D. Voloshina, N. V. Kulik, V. V. Zobov and V. A. Mamedov, Eur. J. Med. Chem., 2013, 66, 345.
16. (a) S. Chuprakov, F. Hwang and V. Gevorgyan, Angew. Chem., Int. Ed., 2007, 46, 4757; (b) Y. Shi, A. V. Gulevich and V. Gevorgyan, Angew. Chem., Int. Ed., 2014, 53, 14191; (c) G. Pelletier and A. B. Charette, Org. Lett., 2013, 15, 2290; (d) M. E. Bluhm, M. Ciesielski, H. Görls and M. Döring, Angew. Chem., Int. Ed., 2002, 41, 2962; (e) S. Fumitoshi, S. Rie, Y. Eiji, K. Asumi and M. Toshiaki, J. Org. Chem., 2009, 74, 3566; (f) M. Li, Y. Xie, Y. Ye, Y. Zou, H. Jiang and W. Zeng, Org. Lett., 2014, 16, 6232; (g) Y. Yan, Y. Zhang, Z. Zha and Z. Wang, Org. Lett., 2013, 15, 2274; (h) S. Fumitoshi, K. Asumi, Y. Eiji and M. Toshiaki, Org. Lett., 2006, 8, 5621; (i) D. S. Roman, V. Poiret, G. Pelletier and A. B. Charette, Eur. J. Org. Chem., 2015, 67.
17. Named Organic Reactions, ed. T. Laue and A. Plagens, John Wiley & Sons, Chichester, England, New York, 2005, vol. 2, p. 320.
18. (a) F. Chen, T. Wang and N. Jiao, Chem. Rev., 2014, 114, 8613; (b) T. Wang and N. Jiao, Acc. Chem. Res., 2014, 47, 1137; (c) C. Tang and N. Jiao, Angew. Chem., Int. Ed., 2014, 53, 6528; (d) P. Feng, X. Sun, Y. Su, X. Li, L. H. Zhang, X. Shi and N. Jiao, Org. Lett., 2014, 16, 3388; (e) Y. Liang, Y. F. Liang and N. Jiao, Org. Chem. Front., 2015, 2, 403.
19. (a) S. B. Han, S. Park, K. Kim and S. Chang, J. Org. Chem., 2008, 73, 2862; (b) K. M. Gillespie, E. J. Crust, R. J. Deeth and P. Scott, Chem. Commun., 2001, 785.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5qo00313j

---