Cite this: RSC Advances, 2013, 3, 11472

Received 11th February 2013,Accepted 15th May 2013

Base and ligand free copper-catalyzed N-arylation of2-amino-N-heterocycles with boronic acids in air3

DOI: 10.1039/c3ra40735g

www.rsc.org/advances

D. Nageswar Rao, Sk. Rasheed, S. Aravinda, Ram A. Vishwakarma*and Parthasarathi Das*

A wide range of N-arylated 2-amino-N-heterocycles were synthe-

sized by a copper-catalyzed boronic acid cross coupling reaction at

ambient temperature in air. This ligand and base free methodol-

ogy is general and could provide rapid access to a diverse array of

potential bioactive heterocyclic compounds.

The presence of 2-amino-N-heterocycles in various natural andsynthetic products has generated interest in medicinal chemistrybecause of their useful biological properties.1 They feature as astructural motif in many top selling drugs (Fig. 1).2 Presentlymarketed drugs, particularly kinase inhibitors (Imatinib,Dasatinib, Pazopanib etc.), with anticancer properties haveN-arylated 2-amino-N-heterocycle motifs.3 A variety of naturalproducts contain these entities.4 2-Amino-N-heterocycles are alsoimportant precursors in the synthesis of hetero aromaticcompounds.5 Therefore, N-arylation of 2-amino-N-heterocyclescan be considered as an important way to synthesize moleculesparticularly with pharmaceutical importance.6

Copper-promoted C–X bond cross-coupling between arylboro-nic acids and HN/HO/HS-containing substrates has recentlyemerged as an important and powerful synthetic methodology.7

The hallmark of this new cross-coupling (Chan–Lam) is the mildreaction conditions, e.g. room temperature, weak base andambient atmosphere (‘open-flask’ chemistry).8 Due to the simpli-city of reaction conditions, and functional group tolerance, thiscopper salt-promoting Chan–Lam coupling has been utilized forthe synthesis of various biologically active heterocyclic compoundsin recent times.9 According to the Chan–Lam observations,electron rich N-nucleophiles tend to give better results, but thepresence of chelating nitrogen can sometimes influence theproduct yield significantly as is observed in case of 2-aminosubstituted pyridine, pyrimidine, pyrazine and thiazole.10 Toovercome this limitation, we describe herein a highly efficient

Cu-catalyzed N-arylation of 2-amino-N-heterocycles with boronicacids under ligand and base free conditions in the presence of air(Scheme 1).11

Our initial experiments on the N-arylation of 2-aminopyridinewith phenylboronic acid using standard Chan–Lam conditions7

resulted only in 20% yield. The screening of different solvents andcopper salts frustrated us with poor yields. However, to ourdelight, we observed the N-arylation between 2-aminopyridine andphenyl boronic acid (2 equiv.) to proceed with completeconversion with Cu(OAc)2 (1 equiv.), and 1,2 dichloroethane assolvent (Table 1 entry 1). N-Phenyl-2-aminopyridine was isolated in80% yield along with 10% biphenyl. No base was required toactivate the amine and the reaction was carried out under open airconditions. In this optimization process, when we reduce theamount of boronic acid from 2.0 to 1.1 equiv., it was observed thatonly 3–5% biphenyl was formed. Encouraged by this finding, weperformed the reaction catalytically and found 10 mol% Cu(OAc)2

Medicinal Chemistry Division, Indian Institute of Integrative Medicine, Canal Road,

Jammu-180001, India. E-mail: partha@iiim.ac.in; ram@iiim.ac.in;

Fax: 91-191-2569019; Tel: 91-191-2560000; IIIM communication no. 1519

3 Electronic supplementary information (ESI) available: Experimental details andspectroscopic data for all compounds. CCDC 909445. For ESI and crystallographicdata in CIF or other electronic format see DOI: 10.1039/c3ra40735g

Fig. 1 Selected examples of N-arylated 2-amino-N-heterocycles with medicinalvalues.

Scheme 1 Copper(II) catalyzed N-arylation of 2-amino-N-heterocycles.

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was sufficient for complete conversion in 4 h and with 90%isolated yield (Table 1, entry 4). Replacement of copper acetatewith different Cu salts could not provide any further improvementin yield, nor could changing the reaction time. A good yield wasonly observed in case of Cu(OTf)2 (Table 1, entry 10), whereas CuOfailed to promote this reaction (Table 1, entry 15). Additionalscreening of different solvents revealed that in the presence ofDCM, MeOH and MeCN the yields are moderate, whereas lowyields were observed in toluene and DMF. Reaction under 1 atmO2 did not further benefit the yield or reduce the reaction time(Table 1, entry 20).

Having identified the optimum reaction conditions (Table 1)we proceeded to explore the scope and limitations of this methodwith various 2-amino-N-heterocycles. First the scope of thisreaction was examined by using 2-aminopyridine with electro-nically diverse boronic acids. Interestingly, all of the examinedsubstrates underwent clean conversion to the desired N-arylatedaminopyridine (70–90%) and the only noticeable difference wasobserved in the reaction time. Substituting at the p- andm-position both electron donating (for example 1b, 1c, 1e, 1n,1p) and electron withdrawing groups (for example 1d, 1h, 1o) gavevery satisfactory yields. It was also discovered that substitution atthe o-position did not have much influence on the yield.2-Methylphenylboronic acid gave 79% (1i) yield.

As expected in the case of strong electron withdrawing groups,like NO2, the isolated yield is 75% (1h), with 15% recovery of2-aminopyridine. Interestingly, thiophen-2-ylboronic acid works

well under these reaction conditions and gave the couplingproduct (1l) in 81% yield. Substrates containing functional groupsthat have been problematic1 in palladium catalyzed aminationchemistry, such as 4-bromo 2-aminopyridine, were successful ingiving clean products (1o and 1p), thereby further illustrating thebroad substrate scope. Two bicyclic boronic acids were alsoinvestigated, in the case of benzo[d][1,3]dioxol-5-ylboronic acid theyield is 89% (1j) whereas 2-naphthylboronic acid resulted in 82%(1k) yield (Table 2).

To enhance the generality of the reaction conditions, different2-amino-N-heterocyclics were subjected to the cross-couplingreaction with different boronic acids. To our delight the optimizedconditions work well in case of 2-aminopyrimidine (Table 3, 2a–e),2-aminopyrazine (2f–h), 2-aminoquinoline (2i–k) and 1-aminoisoquinoline (2l–n).

Reactivity studies with different boronic acids were carried out.Electron donating and electron withdrawing boronic acids workwell across the chemically different substrates. Bicyclic heteroaro-matic systems (2-aminoquinoline and 1-amino isoquinoline) gavebetter yields (79–82%) compared to their monocyclic counterparts(2-aminopyrimidine and 2-aminopyrazine). Chloro (2d) andbromo (2k) derivatives were also synthesized by utilizing thesemild reaction conditions which give the opportunity for furtherfunctionalization of these halo derivatives. Single crystal analysisof 1-aminoisoquinoline derivative (2n) has been studied in thiscontext.12

Both 2-arylaminothiazoles and 2-arylaminobenzothiazoles haveattracted much attention in medicinal chemistry over the pastdecade. Interestingly, during structure–activity relationship (SAR)studies it was observed that a change in the structure ofsubstituent groups at the C-2 position commonly results in a

Table 1 Optimization studies for N-arylation of 2-amino-N-heterocyclesa

Entry Catalyst mol(%) Solvent t (h) Con (%) Yield (%)b

1 Cu(OAc)2 100 DCE 4 100 802 Cu(OAc)2 50 DCE 4 100 823 Cu(OAc)2 20 DCE 4 100 904 Cu(OAc)2 10 DCE 4 100 905 Cu(OAc)2 10 DCM 12 80 706 Cu(OAc)2 10 MeOH 15 90 787 Cu(OAc)2 10 MeCN 12 85 738 Cu(OAc)2 10 Toluene 12 70 509 Cu(OAc)2 10 DMF 12 70 4710 Cu(OTf)2 10 DCE 4 95 8011 Cu(OTf) 50 DCE 4 90 8212 CuI 20 DCE 15 50 1013 CuBr 10 DCE 15 40 1014 CuBr2 10 DCE 15 55 2015 CuO 10 DCE 15 00 0016 CuCl 10 DCE 15 40 1017 CuCl?H2O 10 DCE 15 40 1518 Cu2O 10 DCE 15 50 1519 CuCl2 10 DCE 15 30 1020 Cu(OAc)2 10 DCE 4 100 90c

a Reaction conditions: 2-aminopyridine (1 equiv.), boronic acid (1.1equiv.) Cu(OAc)2 (10 mol%), DCE (2 mL), rt, air. b Isolated yield. c O2

(1 atm) used in place of air.

Table 2 N-Arylation of 2-aminopyridinea

a Reaction conditions: 2-aminopyridine (1 equiv.), boronic acids (1.1equiv.), Cu(OAc)2 (10 mol%), DCE (2 mL), rt, air, 5–14 h. b Recoveredstarting material is indicated in parentheses.

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change in bioactivity.13 Here we have successfully applied thisreaction to the arylation of 2-aminothiazole (3a 3b and 3c) and2-aminobenzothiazole (3d, 3e and 3f) (Table 4). We further appliedthis reaction in synthesizing N-aryl derivatives of anothermedicinally important heterocyclic pyrazolo pyridine.14 1-Alkylsubstituted 1H-pyrazolo[3,4-b]pyridin-3-amine was synthesized15

and subjected to N-arylation using the optimized couplingprotocol. Pyrazolopyridine-3-amine derivatives work smoothly withvarious boronic acids under these coupling conditions (Table 5). Agood yield was observed in the case of simple phenylboronic acid(4a), and 4-cyanophenylboronic acid resulted in moderate yield(4d).

Finally, we applied this methodology in the one pot synthesisof pyrido [1,2-a]benzimidazole from 2-aminopyridine, where thefirst step involves the Cu-catalyzed N-arylation of 2-amino pyridine,

followed by Cu-catalyzed intramolecular C–H amination toproduce pyrido [1,2-a]benzimidazole (5), which employs Fe(III)salts and dioxygen as the terminal oxidant.16 This in situconversion will undoubtedly extend the broad application of thismethodology in synthesizing complex heterocyclics (Scheme 2).

Based on these findings and previous reports17a we put forwarda tentative mechanistic proposal (Scheme 3). The first stepinvolves the rapid co-ordination and dissolution of copper(II)acetate (A). The second step involves trans-metallation whichresults in an arylated Cu(II) complex (B). Then the Cu(II) complex(B) undergoes air oxidation to the Cu(III) state (C), facilitatingsmooth reductive elimination to afford the N-arylated product(1a).17 In this proposed mechanism, O2 (air) is the terminaloxidant. To test this hypothesis, a catalytic reaction was conductedunder a N2 atmosphere, using phenyl boronic acid and2-aminopyridine as the reagents, but only 20% conversion of the

Table 3 N-Arylation of 2-aminopyrimidinea, 2-aminopyrazinea, 2-aminoquinoli-nea, 1-aminoisoquinolinea

a Reaction conditions: 2-aminoheteroaromatic (1 equiv.), boronicacid (1.1 equiv.), Cu(OAc)2 (10 mol%), DCE (2 mL), rt, air, 10–18 h.b Recovered starting material is indicated in parentheses.

Table 4 N-Arylation of 2-aminothiazolea and 2-aminobenzothiazolea

a Reaction conditions: 2-aminothiazole/2-aminobenzothiazole (1equiv.), boronic acid (1.1 equiv.), Cu(OAc)2 (10 mol%), DCE (2 mL),rt, air, 6–15 h. b Recovered starting material is indicated inparentheses.

Table 5 N-Arylation of 1-isopropyl-1H-pyrazolo[3,4-b]pyridin-3-aminea

a Reaction conditions: 3-amino pyrazolopyridine (1 equiv.), boronicacid (1.1 equiv.), Cu(OAc)2 (10 mol%), DCE (2 mL), rt, air, 12–18 h.b Recovered starting material indicated in parentheses.

Scheme 2 One pot synthesis of pyrido[1,2-a]benzimidazole.

Scheme 3 Tentative mechanistic proposal.

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starting material was observed even after a prolonged reactiontime (48 h).

In conclusion, we have developed an efficient Cu-catalyzedprotocol for N-arylation of 2-amino-N-heterocycles, a class ofnucleophiles that have been problematic under previous cross-coupling conditions with arylboronic acids. This transformationcan be performed under air, without the need of a ligand for theCu-catalyst or a base to activate the amine. This ‘open-flask’chemistry is general and the reaction conditions are mildcompared to Pd-catalyzed Buchwald–Hartwig cross-coupling,making it a very attractive tool for the synthesis of variousheterocyclics. Thus this procedure further extends the usefulnessof Cu-catalyzed cross-coupling reactions in the fast growing field ofN-arylation chemistry.

D.N.R and Sk. R thank UGC and CSIR-New Delhi for researchfellowships, respectively.

Notes and references1 T. R. M. Rauws and B. U. W. Maes, Chem. Soc. Rev., 2012, 41,

2463.2 http://www.drugs.com/top200html, Pharmaceutical Sales 2010.3 (a) S. Agarwal, Nat. Rev. Drug Discovery, 2010, 9, 427; (b)

A. Bikker, M. Brooijmans, A. Wissner and T. S. Mansour, J. Med.Chem., 2009, 52, 1493.

4 R. G. S. Berlinck and M. H. Kossuga, Modern Alkaloids, Wiley-VCH Verleg GmbH & Co. KGaA, 2007, pp. 305–337.

5 (a) M. A. McGowan, C. Z. McAvoy and S. L. Buchwald, Org. Lett.,2012, 14, 3800; (b) J. E. Taylor, S. D. Bull and J. M. J. Williams,Chem. Soc. Rev., 2012, 41, 2109.

6 J. Li, S. Benard, L. Neuville and J. Zhu, Org. Lett., 2012, 14, 5980.7 (a) D. M. T. Chan, K. L. Monaco, R. P. Wang and M. P. Winters,

Tetrahedron Lett., 1998, 39, 2933; (b) P. Y. S. Lam, C. G. Clark,S. Saubern, J. Adams, M. P. winters, D. M. T. Chan and

A. Combs, Tetrahedron Lett., 1998, 39, 2941; (c) J. P. Collmanand M. Zhong, Org. Lett., 2000, 2, 1233; (d) P. Y. S. Lam, G.C. Clark, S. Saubern, J. Adams, K. M. Averill, D. M. T. Chan andA. Combs, Synlett, 2000, 674.

8 (a) S. V. Ley and A. W. Thomas, Angew. Chem., Int. Ed., 2003, 42,5400; (b) J. X. Qiao and P. Y. S. Lam, Synthesis, 2011, 829; (c) K.S. Rao and T. S. Wu, Tetrahedron, 2012, 68, 7735.

9 (a) R. Adepu, K. Shivakumar, S. Sandra, D. Rambabu,G. Ramakrishna, C. Mallareddy, A. Kandale, P. Misra andM. Pal, Bioorg. Med. Chem., 2012, 20, 5127; (b)K. Sreeramamurthy, E. Ashok, V. Mahinder, G. Santoshkumarand P. Das, Synlett, 2010, 721; (c) I. Gonzalez, J. Mosquera,C. Guerrero, R. Rodriguez and J. Cruces, Org. Lett., 2009, 11,1677.

10 D. M. T. Chan and P. Y. S. Lam, in Boronic Acids: Preparationand Application in Organic Synthesis and Medicine, ed. D. G. Hall,Wiley-VCH, 2006, pp. 205–240.

11 (a) T. D. Quach and R. A. Batey, Org. Lett., 2003, 5, 4397; (b)B. Kaboudin, Y. Abedi and T. Yokomatsu, Eur. J. Org. Chem.,2011, 6656.

12 Details of X-ray (CCDC No. 909445) analysis is given in thesupporting information (ESI3).

13 Y. Lu, C.-M. Li, Z. Wang, J. Chen, M. L. Mohler, W. Li, J.T. Dalton and D. D. Miller, J. Med. Chem., 2011, 54, 4678.

14 R. Gomez, S. J. Jolly, T. Williams, J. P. Vacca and M. Torrent, J.Med. Chem., 2011, 54, 7920.

15 See the supporting information (ESI3) for the synthesis ofN-alkyl pyrazolopyridine.

16 H. Wang, Y. Wang, C. Peng, J. Zhang and Q. Zhu, J. Am. Chem.Soc., 2010, 132, 13217.

17 (a) P. Y. S. Lam, D. Bonne, G. Vicent, C. G. Clark and A.P. Combs, Tetrahedron Lett., 2003, 44, 1691; (b) A. E. King, L.M. Huffman, A. Casitas, M. Costas, X. Ribas and S. S. Stahl, J.Am. Chem. Soc., 2010, 132, 12068; (c) Z. Shi, C. Zhang, C. Tangand N. Jiao, Chem. Soc. Rev., 2012, 41, 3381.

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