Synthesis 2023; 55(21): 3535-3567
DOI: 10.1055/a-2056-2363
special topic
C–H Bond Functionalization of Heterocycles

Pd(II)-Catalyzed Directing-Group-Aided C–H Arylation, Alkylation, Benzylation, and Methoxylation of Carbazole-3-carboxamides toward C2,C3,C4-Functionalized Carbazoles

Ramandeep Kaur
,
Harcharan Singh
,
S.A.B. thanks the Indian Institute of Science Education and Research (IISER), Mohali for funding. R.D. thanks IISER Mohali and H.S. thanks the University Grants Commission (UGC), New Delhi for providing PhD fellowships.


Abstract

We report the Pd(II)-catalyzed β-C–H arylation, alkylation, benzylation, and methoxylation of carbazole-3-carboxamide and carbazole-2-carboxamide substrates, assisted by the bidentate directing groups 8-aminoquinoline or 2-(methylthio)aniline, and construction of C2,C3,C4-functionalized carbazole motifs. The Pd(II)-catalyzed β-C–H arylation reaction was attempted using different directing groups such as 8-aminoquinoline, 2-(methylthio)aniline, 4-amino-2,1,3-benzothiadiazole, 4-methoxyquinolin-8-amine, and butan-1-amine. Through optimization of the reactions, 8-aminoquinoline and 2-(methylthio)aniline were found to be suitable directing groups and, especially, 2-(methylthio)aniline was found to be an efficient directing group in the Pd(II)-catalyzed β-C–H arylation, alkylation, and methoxylation of carbazole-3-carboxamide, carbazole-2-carboxamide substrates. An ample number of β-C–H arylated, alkylated, benzylated, and methoxylated carbazole-3-carboxamides were synthesized. The structures of representative β-C(2)–H arylated carbazole and β-C(2)–H methoxylated carbazole motifs were unequivocally confirmed by single-crystal X-ray structure analysis. Given the wide range of applications of carbazoles in chemistry, materials sciences, and medicinal chemistry and there have been constant efforts for developing new methods for synthesizing functionalized carbazoles. This work contributes to the expansion of the library of C2,C3,C4-functionalized carbazole motifs through a Pd(II)-catalyzed directing-group-aided site-selective β-C–H activation and functionalization of carbazole-3-carboxamides.

Supporting Information



Publication History

Received: 30 December 2022

Accepted after revision: 16 March 2023

Accepted Manuscript online:
16 March 2023

Article published online:
08 May 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References


    • For selected reviews on C–H functionalization, see:
    • 1a Kakiuchi F, Murai S. Acc. Chem. Res. 2002; 35: 826
    • 1b Hirano K, Miura M. Chem. Lett. 2015; 44: 868
    • 1c Lyons TW, Sanford MS. Chem. Rev. 2010; 110: 1147
    • 1d Colby DA, Bergman RG, Ellman JA. Chem. Rev. 2010; 110: 624
    • 1e Wang W, Lorion MM, Shah J, Kapdi AR, Ackermann L. Angew. Chem. Int. Ed. 2018; 57: 14700
    • 1f Rej S, Das A, Chatani N. Coord. Chem. Rev. 2021; 431: 213683
    • 1g Zhu R.-Y, Farmer ME, Chen Y.-Q, Yu J.-Q. Angew. Chem. Int. Ed. 2016; 55: 10578
    • 1h Yoshino T, Matsunaga S. Adv. Synth. Catal. 2017; 359: 1245
    • 1i Higham JI, Bull JA. Org. Biomol. Chem. 2020; 18: 7291
    • 1j Banerjee A, Sarkar S, Patel B. Org. Biomol. Chem. 2017; 15: 505
    • 1k Bag S, Maiti D. Synthesis 2016; 48: 804
    • 1l Yamaguchi J, Yamaguchi AD, Itami K. Angew. Chem. Int. Ed. 2012; 51: 8960
    • 1m Uttry A, van Gemmeren M. Synthesis 2020; 52: 479
    • 1n Arockiam PA, Bruneau C, Dixneuf PH. Chem. Rev. 2012; 112: 5879
    • 1o Besset T, Poisson T, Pannecoucke X. Chem. Eur. J. 2014; 20: 16830
    • 1p Sinha SK, Guin S, Maiti S, Biswas JP, Porey S, Maiti D. Chem. Rev. 2022; 122: 5682

    • For themed issues on C–H activation, see:
    • 1q Crabtree RH, Lei A. Chem. Rev. 2017; 117: 8481
    • 1r Davies HM. L, Bois J, Yu J.-Q. Chem. Soc. Rev. 2011; 40: 1855
    • 2a Zu B, Guo Y, Ke J, He C. Synthesis 2021; 53: 2029
    • 2b Talukdar K, Shah TA, Sarkar T, Roy S, Maharana PK, Punniyamurthy T. Chem. Commun. 2021; 57: 13221
    • 2c Babu SA, Padmavathi R, Suwasia S, Dalal A, Bhattacharya D, Singh P, Tomar R. Stud. Nat. Prod. Chem. 2021; 71: 311
    • 2d Gensch T, Hopkinson MN, Glorius F, Wencel-Delord J. Chem. Soc. Rev. 2016; 45: 2900
    • 2e Jazzar R, Hitce J, Renaudat A, Sofack-Kreutzer J, Baudoin O. Chem. Eur. J. 2010; 16: 2654
    • 2f Yang K, Song M, Liu H, Ge H. Chem. Sci. 2020; 11: 12616
    • 2g Subramanian P, Rudolf GC, Kaliappan KP. Chem. Asian J. 2016; 11: 168
    • 2h Yorimitsu H, Yoshimura A, Misaki Y. Synthesis 2020; 52: 3326
    • 2i Manikandan R, Jeganmohan M. Chem. Commun. 2017; 53: 8931
    • 2j Saito H, Yamamoto K, Sumiya Y, Liu L.-J, Nogi K, Maeda S, Yorimitsu H. Chem. Asian J. 2020; 15: 2442
    • 2k Manoharan R, Jeganmohan M. Asian J. Org. Chem. 2019; 8: 1949
    • 2l Das R, Kumar GS, Kapur M. Eur. J. Org. Chem. 2017; 5439
    • 2m Babu SA, Aggarwal Y, Patel P, Tomar R. Chem. Commun. 2022; 58: 2612
    • 2n Maraswami M, Loh T.-P. Synthesis 2019; 51: 1049
    • 2o Patel OP. S, Nandwana NK, Legoabe LJ, Das BC, Kumar A. Adv. Synth. Catal. 2020; 362: 4226
    • 2p Babu SA, Padmavathi R, Aggarwal Y, Kaur R, Suwasia S. Pd-Catalyzed C(sp3)–H Activation by Native Directing Groups . In Handbook of CH-Functionalization . Maiti D. Wiley-VCH; Weinheim: 2022
    • 2q Dutta S, Bhattacharya T, Geffers FJ, Bürger M, Maiti D, Werz DB. Chem. Sci. 2022; 13: 2551

      For selected reviews on bidentate directing-group-aided C–H functionalization, see:
    • 3a Rej S, Ano Y, Chatani N. Chem. Rev. 2020; 120: 1788
    • 3b Rouquet G, Chatani N. Angew. Chem. Int. Ed. 2013; 52: 11726
    • 3c Daugulis O, Roane J, Tran LD. Acc. Chem. Res. 2015; 48: 1053
    • 3d Liu B, Romine AM, Rubel CZ, Engle KM, Shi B.-F. Chem. Rev. 2021; 121: 14957
    • 3e Yadav MR, Rit RK, Majji S, Sahoo AK. Asian. J. Org. Chem. 2015; 4: 846
    • 3f Sambiagio C, Schönbauer D, Blieck R, Dao-Huy T, Pototschnig G, Schaaf P, Wiesinger T, Zia MF, Wencel-Delord J, Besset T, Maes BU. W, Schnürch M. Chem. Soc. Rev. 2018; 47: 6603
    • 3g He G, Wang B, Nack WA, Chen G. Acc. Chem. Res. 2016; 49: 635
    • 3h Noisier AF. M, Brimble MA. Chem. Rev. 2014; 114: 8775
    • 3i Yang X, Shan G, Wang L, Rao Y. Tetrahedron Lett. 2016; 57: 819
    • 3j Rit RK, Yadav MR, Ghosh K, Sahoo AK. Tetrahedron 2015; 71: 4450
    • 3k Li H, Li B.-J, Shi Z.-J. Catal. Sci. Technol. 2011; 1: 191
    • 4a Negishi E.-i. Angew. Chem. Int. Ed. 2011; 50: 6738
    • 4b Suzuki A. Angew. Chem. Int. Ed. 2011; 50: 6722
    • 4c Heck RF. Acc. Chem. Res. 1979; 12: 146
    • 4d Johansson SC, Kitching M, Colacot T, Snieckus V. Angew. Chem. Int. Ed. 2012; 51: 5062
    • 4e Nicolaou KC, Bulger PG, Sarlah D. Angew. Chem. Int. Ed. 2005; 44: 4442
    • 4f Sestelo JP, Sarandeses LA. Molecules 2020; 25: 4500
    • 4g de Meijere A, Bräse S, Oestreich M. Metal-Catalyzed Cross-Coupling Reactions and More, 1st ed. Wiley-VCH; Weinheim: 2014
    • 4h Molnár A. Palladium-Catalyzed Coupling Reactions, 1st ed. Wiley-VCH; Weinheim: 2013

      For selected papers on directing-group-aided C–H functionalization, see:
    • 5a Shabashov D, Daugulis O. J. Am. Chem. Soc. 2010; 132: 3965
    • 5b He G, Chen G. Angew. Chem. Int. Ed. 2011; 50: 5192
    • 5c He J, Wasa M, Chan KS. L, Yu J.-Q. J. Am. Chem. Soc. 2013; 135: 3387
    • 5d Wang Z, Kuninobu Y, Kanai M. Org. Lett. 2014; 16: 4790
    • 5e Hoshiya N, Kondo M, Fukuda H, Arisawa M, Uenishi J, Shuto S. J. Org. Chem. 2017; 82: 2535
    • 5f Xu J.-W, Zhang Z.-Z, Rao W.-H, Shi B.-F. J. Am. Chem. Soc. 2016; 138: 10750
    • 5g Zeng W, Nukeyeva M, Wang Q, Jiang C. Org. Biomol. Chem. 2018; 16: 598
    • 5h Song J, Chen W, Zhao Y, Li C, Liang G, Huang L. RSC Adv. 2016; 6: 54984
    • 5i Seki A, Takahashi Y. Tetrahedron Lett. 2021; 74: 153130
    • 5j Zhang S.-K, Yang X.-Y, Zhao X.-M, Li P.-X, Niu J.-L, Song M.-P. Organometallics 2015; 34: 4331
    • 5k Ghouilem J, Tran C, Grimblat N, Retailleau P, Alami M, Gandon V, Messaoudi S. ACS Catal. 2021; 11: 1818
    • 5l Aihara Y, Chatani N. ACS Catal. 2016; 6: 4323
    • 5m Xiong H.-Y, Cahard D, Pannecoucke X, Besset T. Eur. J. Org. Chem. 2016; 3625
    • 5n Gou Q, Zhang Z.-F, Liu Z.-C, Qin J. J. Org. Chem. 2015; 80: 3176
    • 5o Pradhan S, De PB, Punniyamurthy T. J. Org. Chem. 2017; 82: 4883
    • 5p Song H, Li Y, Yao Q.-J, Shi B.-F. Org. Chem. Front. 2022; 9: 4823
    • 5q Milbauer MW, Kampf JW, Sanford MS. J. Am. Chem. Soc. 2022; 144: 21030
    • 5r Bay KL, Yang Y.-F, Houk KN. J. Organomet. Chem. 2018; 864: 19
    • 5s Hu Y, Wang M, Li P, Li H, Wang L. Asian. J. Org. Chem. 2019; 8: 171

      For selected papers from our laboratory on bidentate DG-aided C–H functionalization, see:
    • 6a Reddy C, Bisht N, Parella R, Babu SA. J. Org. Chem. 2016; 81: 12143
    • 6b Padmavathi R, Sankar R, Gopalakrishnan B, Parella R, Babu SA. Eur. J. Org. Chem. 2015; 3727
    • 6c Parella R, Babu SA. J. Org. Chem. 2017; 82: 7123
    • 6d Bisht N, Babu SA, Tomar R. Asian. J. Org. Chem. 2020; 9: 1225
    • 6e Naveen, Rajkumar V, Babu SA, Gopalakrishnan B. J. Org. Chem. 2016; 81: 12197
    • 6f Banga S, Kaur R, Babu SA. Eur. J. Org. Chem. 2021; 3641
    • 6g Padmavathi R, Babu SA. Asian. J. Org. Chem. 2019; 8: 899
    • 6h Dalal A, Babu SA. Synthesis 2021; 53: 3307
    • 6i Parella R, Babu SA. J. Org. Chem. 2017; 82: 6550
    • 6j Gopalakrishnan B, Mohan S, Parella R, Babu SA. J. Org. Chem. 2016; 81: 8988
    • 6k Parella R, Babu SA. J. Org. Chem. 2015; 80: 12379
    • 6l Parella R, Babu SA. J. Org. Chem. 2015; 80: 2339
    • 6m Parella R, Gopalakrishnan B, Babu SA. Org. Lett. 2013; 15: 3228
    • 6n Singh P, Dalal A, Babu SA. Asian. J. Org. Chem. 2019; 8: 877
    • 6o Tomar R, Kumar A, Dalal A, Bhattacharya D, Singh P, Babu SA. Asian. J. Org. Chem. 2022; 11: e202200311
    • 6p Bisht N, Singh P, Babu SA. Synthesis 2022; 54: 4059
    • 6q Bisht N, Babu SA, Tomar R. Asian. J. Org. Chem. 2022; 11: e202200589

      For selected reviews dealing with carbazoles and their applications, see:
    • 7a Schmidt AW, Reddy KR, Knölker H.-J. Chem. Rev. 2012; 112: 3193
    • 7b Bergman J, Pelcman B. Pure Appl. Chem. 1990; 62: 1967
    • 7c Xubin F, Lei F, Shaohua G. Chin. J. Org. Chem. 2012; 32: 1217
    • 7d Zhang W, Ready JM. Nat. Prod. Rep. 2017; 34: 1010
    • 7e Banerjee A, Kundu S, Bhattacharyya A, Sahu S, Maji MS. Org. Chem. Front. 2021; 8: 2710
    • 7f Mandal T, Dash J. Org. Biomol. Chem. 2021; 19: 9797
    • 7g Aggarwal T, Sushmita Verma AK. Org. Biomol. Chem. 2019; 17: 8330
    • 7h Roy J, Jana AK, Mal D. Tetrahedron 2012; 68: 6099
    • 7i Obora Y. Tetrahedron Lett. 2018; 59: 167

      For selected reviews dealing with applications of carbazoles in materials chemistry, see:
    • 8a Jiang H. Asian. J. Org. Chem. 2014; 3: 102
    • 8b Yin J, Ma Y, Li G, Peng M, Lin W. Coord. Chem. Rev. 2020; 412: 213257
    • 8c Dumur F. Eur. Polym. J. 2020; 125: 109503
    • 8d Wex B, Kaafarani BR. J. Mater. Chem. C 2017; 5: 8622
    • 8e Ledwon P. Org. Electron. 2019; 75: 105422
    • 8f Manickam M, Iqbal P, Belloni M, Kumar S, Preece JA. Isr. J. Chem. 2012; 52: 917

      For selected reviews/papers dealing with bio-active carbazoles, see:
    • 9a Głuszyńska A. Eur. J. Med. Chem. 2015; 94: 405
    • 9b Caruso A, Ceramella J, Iacopetta D, Saturnino C, Mauro MV, Bruno R, Aquaro S, Sinicropi MS. Molecules 2019; 24: 1912
    • 9c Issa S, Prandina A, Bedel N, Rongved P, Yous S, Borgne ML, Bouaziz Z. J. Enzyme Inhib. Med. Chem. 2019; 34: 1321
    • 9d Caruso A, Barbarossa A, Carocci A, Salzano G, Sinicropi MS, Saturnino C. Appl. Sci. 2021; 11: 6192
    • 9e Spandana Z, Sreenivasulu R, Rao MV. B. Lett. Org. Chem. 2019; 16: 662
    • 9f Wang G, Sun S, Guo H. Eur. J. Med. Chem. 2022; 229: 113999
    • 9g Venkatesh Y, Rajesh Y, Karthik S, Chetan AC, Mandal M, Jana A, Singh ND. P. J. Org. Chem. 2016; 81: 11168
    • 9h Wang W, Li J, Yao J, Wang T, Li S, Zheng X, Duan L, Zhang W. J. Antimicrob. Chemother. 2017; 72: 3122
    • 9i Ghobadian R, Nadri H, Moradi A, Bukhari SN. A, Mahdavi M, Asadi M, Akbarzadeh T, Khaleghzadeh-Ahangar H, Sharifzadeh M, Amini M. Bioorg. Med. Chem. 2018; 26: 4952
    • 9j Fang L, Chen M, Liu Z, Fang X, Gou S, Chen L. Bioorg. Med. Chem. 2016; 24: 886
    • 9k Thiratmatrakul S, Yenjai C, Waiwut P, Vajragupta O, Reubroycharoen P, Tohda M, Boonyarat C. Eur. J. Med. Chem. 2014; 75: 21
    • 9l Meng F, Liu Y, Yu X, Lin W. New J. Chem. 2016; 40: 7399
    • 9m Sadeghian B, Sakhteman A, Faghih Z, Nadri H, Edraki N, Iraji A, Sadeghian I, Rezaei Z. J. Mol. Struct. 2020; 1221: 128793
    • 9n You X, Zhu D, Lu W, Sun Y, Qiao S, Luo B, Du Y, Pi R, Hu Y, Huang P, Wen S. RSC Adv. 2018; 8: 17183
    • 9o Diaz P, Horne E, Xu C, Hamel E, Wagenbach M, Petrov RR, Uhlenbruck B, Hass B, Hothi P, Wordeman L, Gussio R, Stella N. Eur. J. Med. Chem. 2018; 159: 74 ; here the preparation of compound 22d (9-ethyl-2-methoxy-9H-carbazole) is reported. It appears that the NMR signals do not correspond to our NMR prediction, e.g., it revealed the presence of four signals in the range δ = 0–55 in the 13C NMR spectrum and also two independent singlet signals at δ = 3.96 and 3.93 in the 1H NMR spectrum for the (expected one) OMe group (the presence of six aromatic protons is also accounted for in the 1H NMR spectrum). However, compound 22d is expected to give only three signals in the range δ = 0–55 in the 13C NMR spectrum and also only one singlet signal around δ = 3.91 ppm in the 1H NMR spectrum for the expected single OMe group (in this case, signals accounting for seven aromatic protons are expected); this is also what we observed.

      For selected papers dealing with the synthesis of substituted carbazoles, see:
    • 10a Chen S, Li Y, Ni P, Huang H, Deng G.-J. Org. Lett. 2016; 18: 5384
    • 10b Wang J, Zhu H.-T, Qiu Y.-F, Niu Y, Chen S, Li Y.-X, Liu X.-Y, Liang Y.-M. Org. Lett. 2015; 17: 3186
    • 10c Qiu Y, Kong W, Fu C, Ma S. Org. Lett. 2012; 14: 6198
    • 10d Qiao Y, Wu X.-X, Zhao Y, Sun Y, Li B, Chen S. Adv. Synth. Catal. 2018; 360: 2138
    • 10e Sreenivas DK, Nagarajan R. Tetrahedron 2010; 66: 9650
    • 10f Debnath S, Das T, Pati TK, Majumdar S, Maiti DK. J. Org. Chem. 2020; 85: 13272
    • 10g Chen S, Wang L, Zhang J, Hao Z, Huang H, Deng G.-J. J. Org. Chem. 2017; 82: 11182
    • 10h Ackermann L, Althammer A, Mayer P. Synthesis 2009; 3493
    • 10i Liu Z, Larock RC. Org. Lett. 2004; 6: 3739
    • 10j González JF, Rocchi D, Tejero T, Merino P, Menéndez JC. J. Org. Chem. 2017; 82: 7492
    • 10k Rasheed S, Rao DN, Reddy KR, Aravinda S, Vishwakarma RA, Das P. RSC Adv. 2014; 4: 4960
    • 10l Ozaki K, Zhang H, Ito H, Lei A, Itami K. Chem. Commun. 2013; 4: 3416

      For selected papers on carbazoles via C–H amination, see:
    • 11a Nack WA, Chen G. Synlett 2015; 26: 2505
    • 11b Suzuki C, Hirano K, Satoh T, Miura M. Org. Lett. 2015; 17: 1597
    • 11c Jordan-Hore JA, Johansson CC. C, Gulias M, Beck EM, Gaunt MJ. J. Am. Chem. Soc. 2008; 130: 16184
    • 11d Tsang WC. P, Zheng N, Buchwald SL. J. Am. Chem. Soc. 2005; 127: 14560
    • 11e Monguchi Y, Okami H, Ichikawa T, Nozaki K, Maejima T, Oumi Y, Sawama Y, Sajiki H. Adv. Synth. Catal. 2016; 358: 3145
    • 11f Bal A, Maiti S, Mal P. J. Org. Chem. 2018; 83: 11278
    • 11g Polley A, Varalaxmi K, Jana R. ACS Omega 2018; 3: 14503
    • 11h Antonchick AP, Samanta R, Kulikov K, Lategahn J. Angew. Chem. Int. Ed. 2011; 50: 8605
    • 11i Cho SH, Yoon J, Chang S. J. Am. Chem. Soc. 2011; 133: 5996
    • 11j Youn SW, Bihn JH, Kim BS. Org. Lett. 2011; 13: 3738

      For selected papers dealing with the synthesis of substituted carbazoles, see:
    • 12a Samala S, Shin J, Shim JY, Yoo EJ. Asian. J. Org. Chem. 2017; 6: 998
    • 12b Morita T, Satoh T, Miura M. Org. Lett. 2015; 17: 4384
    • 12c Okada T, Nobushige K, Satoh T, Miura M. Org. Lett. 2016; 18: 1150
    • 12d Urones B, Arrayás RG, Carretero JC. Org. Lett. 2013; 15: 1120
    • 12e Chu J.-H, Wu C.-C, Chang D.-H, Lee Y.-M, Wu M.-J. Organometallics 2013; 32: 272
    • 12f Liyu J, Sperry J. Tetrahedron Lett. 2017; 58: 1699
    • 12g Louillat M.-L, Patureau F. Org. Lett. 2013; 15: 164
    • 12h Leitch JA, Heron CJ, McKnight J, Kociok-Köhn G, Bhonoah Y, Frost CG. Chem. Commun. 2017; 53: 13039
    • 12i Qiu R, Reddy VP, Iwasaki T, Kambe N. J. Org. Chem. 2015; 80: 367
    • 12j Reddy VP, Qiu R, Iwasaki T, Kambe N. Org. Lett. 2013; 15: 1290
    • 12k Reddy KH. V, Kumar RU, Reddy VP, Satish G, Nanubolu JB, Nageswar YV. D. RSC Adv. 2016; 6: 54431
    • 12l Uemura T, Yamaguchi M, Chatani N. Angew. Chem. Int. Ed. 2016; 55: 3162
    • 12m Aihara Y, Wuelbern J, Chatani N. Bull. Chem. Soc. Jpn. 2015; 88: 438
    • 12n Castro LC. M, Obata A, Aihara Y, Chatani N. Chem. Eur. J. 2016; 22: 1362
    • 12o Mandal A, Garai B, Dana S, Bera R, Baidya M. Chem. Asian J. 2020; 15: 4009
    • 13a Shi H.-p, Dai J.-x, Xu L, Shi L.-w, Fang L, Shuang S.-m, Dong C. Org. Biomol. Chem. 2012; 10: 3852
    • 13b Chen PZ, Weng Y.-X, Niu L.-Y, Chen Y.-Z, Wu L.-Z, Tung C.-H, Yang Q.-Z. Angew. Chem. Int. Ed. 2016; 55: 2759
    • 13c Ali MH, Buchwald SL. J. Org. Chem. 2001; 66: 2560
    • 13d Liegault B, Lee D, Huestis MP, Stuart DR, Fagnou K. J. Org. Chem. 2008; 73: 5022
    • 13e Freeman AW, Urvoy M, Criswell ME. J. Org. Chem. 2005; 70: 5014
    • 13f Diaz JL, Dobarro A, Villacampa B, Velasco D. Chem. Mater. 2001; 13: 2528
    • 13g Curiel D, Sánchez G, de Arellano CR, Tárraga A, Molina P. Org. Biomol. Chem. 2012; 10: 1896
  • 14 Zhao Y, Chen G. Org. Lett. 2011; 13: 4850 . The Pd(II)-catalyzed benzylation/alkylation reactions were performed using K2CO3 and NaOTf as the additives (conditions reported by Chen). In general, the usage of K2CO3 alone is believed to function as an iodide ion scavenger and help to regenerate the Pd(II) catalyst in the catalytic cycle. Chen indicated that NaOTf functions as a non-nucleophilic ligand to promote the C–H alkylation with a minimum loading of Pd(II) catalyst and efficient catalyst regeneration in the catalytic cycle. Thus, the combined usage of K2CO3 and NaOTf as the additives gave the C–H alkylated product in good yield. Therefore, we also performed the benzylation/alkylation using K2CO3 and NaOTf as the additives

    • For selected articles dealing with C–H alkoxylation reactions, see:
    • 15a Zheng Q, Chen J, Rao G.-W. Russ. J. Org. Chem. 2019; 55: 569
    • 15b Vijayakumar M, Punji B. Synthesis 2021; 53: 2935
    • 15c Bras JL, Muzart J. Eur. J. Org. Chem. 2018; 1176
    • 15d Aggarwal Y, Padmavathi R, Singh P, Babu SA. Asian. J. Org. Chem. 2022; 11: e202200327
  • 16 Wang and Wang reported5s the CuI-catalyzed C–H alkoxylation of benzamides and proposed a mechanism for the C–H alkoxylation via the Cu(II) species. It is believed that DBU functions as an efficient organic base in promoting the Cu(II) species generation step with the removal of the NH proton from the amide moiety (and it also may have an additional role).
  • 17 CCDC 2233500 (8b) and CCDC 2233501 (21a) contain the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures