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Synlett
DOI: 10.1055/s-0042-1751537
DOI: 10.1055/s-0042-1751537
letter
Evaluation of Phenyldiazenyl as a Protective/Activating Group in Lithiation–Substitution Reactions of Tetrahydroisoquinolines
We acknowledge financial support from the Council of Scientific and Industrial Research (CSIR), India through Scheme number 02(0131)/13/EMR-II. Babaldeep Kaur thanks CSIR for the award of research fellowships.
Abstract
Phenyldiazenyl moiety has been utilized both as a protective and activating group to synthesize C-1-substituted tetrahydroisoquinolines via lithiation–substitution strategy. This reaction sequence involves generation of α-amino carbanions, derived from N-phenyldiazenyl tetrahydroisoquinolines, followed by coupling with various electrophiles, e.g., aldehyde, ketones, alkyl halide, oxiranes, isocyanates, and with in situ generated arynes. Deprotection of the protecting group was carried out under acidic conditions to afford the desired α-substituted products in moderate to good yields. So, triazene as a protecting/directing group and its compatibility with strong bases provide a good synthetic utility for the synthesis of a variety of α-substituted secondary amines via lithiation substitution reaction.
Key words
phenyldiazene - α-C–H functionalization - C-1-substituted THIQs - α-amino carbanions - electrophiles - nitrogen heterocyclesSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0042-1751537.
- Supporting Information
Publication History
Received: 20 April 2023
Accepted after revision: 07 November 2023
Article published online:
19 December 2023
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References and Notes
- 1 Welsch ME, Snyder SA, Stockwell BR. Curr. Opinion Chem. Biol. 2010; 14: 347
- 2a For a review on Csp3@H bond functionalization adjacent to nitrogen, see: Campos KR. Chem. Soc. Rev. 2007; 36: 1069
- 2b Liu G.-Q, Opatz T. Adv. Heterocycl. Chem. 2018; 125: 107
- 3 Lin H.-R, Safo MK, Abraham DJ. Bioorg. Med. Chem. Lett. 2007; 17: 2581
- 4 Mohler ML, Kang G.-S, Hong S.-S, Patil R, Kirichenko OV, Li W, Rakov IM, Geisert EE, Miller DD. J. Med. Chem. 2006; 49: 5845
- 5 Choquette D, Teffera Y, Polverino A, Harmange J.-C. Bioorg. Med. Chem. Lett. 2008; 18: 4054
- 6 Hu M.-K, Liao Y.-F, Chen J.-F, Wang B.-J, Tung Y.-T, Lin H.-C, Lee K.-P. Bioorg. Med. Chem. 2008; 16: 1957
- 7 Azukizawa S, Kasai M, Takahashi K, Miike K, Kunishiro K, Kanda M, Mukai C, Shirahase H. Chem. Pharm. Bull. 2008; 56: 335
- 8 Lin M, Chueh F, Hsieh M, Chen C. Clin. Exp. Pharmacol. Physiol. 1996; 23: 738
- 9 Barbosa-Filho JM, PiuvezamM R, Moura MD, Silva MS, Lima KV. B, Cunha EV. L, Fechine IM, Takemura OS. Rev. Bras. Farmacogn. 2006; 16: 109
- 10 Qian LiuY, Yang L, Tian X. Curr. Bioact. Compd. 2007; 3: 37
- 11 Scott JD, Williams RM. Chem. Rev. 2002; 102: 1669
- 12 Chan JD, Cupit PM, Gunaratne GS, McCorvy JD, Yang Y, Stoltz K, Webb TR, Dosa PI, Roth BL, Abagyan R, Cunningham C, Marchant JS. Nat. Commun. 2017; 8: 1910
- 13 Kaufman TS. Tetrahedron: Asymmetry 2004; 15: 1203
- 14 Chuliá S, Ivorra MD, Lugnier C, Vila E, Noguera MA, D’Ocon P. Br. J. Pharmacol. 1994; 113: 1377
- 15 Tashrifi Z, Khanaposhtani MM, Larijani B, Mahdavi M. Asian J. Org. Chem. 2021; 10: 2421
- 16a Chrzanowska M, Rozwadowska MD. Chem. Rev. 2004; 104: 3341
- 16b Chang M, Li W, Zhang X. Angew. Chem. Int. Ed. 2011; 50: 10679 ; Angew. Chem. 2011, 123, 10867
- 16c Ruzic M, Pecavar A, Prudic D, Kralj D, Scriban C, Zanotti-Gerosa A. Org. Process Res. Dev. 2012; 16: 1293
- 16d Berhal F, Wu Z, Zhang Z, Ayad T, Ratovelomanana-Vidal V. Org. Lett. 2012; 14: 3308
- 17 Ortiz Villamizar MC, Puerto Galvis CE, Kouznetsov VV. In Heterocycles via Cross Dehydrogenative Coupling . Srivastava A, Jana CK. Springer; Singapore: 2019: 7
- 18 Li Z, Li C.-J. J. Am. Chem. Soc. 2005; 127: 6968
- 19 Ghobrial M, Harhammer K, Mihovilovic MD, Schnürch M. Chem. Commun. 2010; 8836
- 20 Jones KM, Karier P, Klussmann M. ChemCatChem 2012; 4: 51
- 21 Alagiri K, Devadig P, Prabhu KR. Chem. Eur. J. 2012; 18: 5160
- 22 Tanwar L, Borgel J, Ritter T. J. Am. Chem. Soc. 2019; 141: 17983
- 23 Li F, Tian D, Fan Y, Lee R, Lu G, Yin Y, Qiao B, Zhao X, Xiao Z, Jiang Z. Nat. Commun. 2019; 10: 1774
- 24 Prier CK, Zhang RK, Buller AR, Brinkmann-Chen S, Arnold FH. Nat. Chem. 2017; 9: 629
- 25 Wong JY. F, Barker G. Tetrahedron 2020; 76: 131704
- 26 Kessar SV, Vohra R, Kaur NP. Tetrahedron Lett. 1991; 32: 3221
- 27 Kessar SV, Singh P, Vohra R, Kaur NP, Singh KN. J. Chem. Soc., Chem. Commun. 1991; 568
- 28 Ebden MR, Simpkins NS, Fox DN. A. Tetrahedron 1998; 54: 12923
- 29 Li X, Leonori D, Sheikh N S, Coldham I. Chem. Eur. J. 2013; 7724
- 30 Li X, Coldham I. J. Am. Chem. Soc. 2014; 5551
- 31 Talk RA, Duperray A, Li X, Coldham I. Org. Biomol. Chem. 2016; 4908
- 32 Gawley RE, Hart G, Goicoechea-Pappas M, Smith AL. J. Org. Chem. 1986; 51: 3076
- 33 Rein K, Goicoechea Pappas M, Anklekar TV, Hart GC, Smith GA, Gawley RE. J. Am. Chem. Soc. 1989; 111: 2211
- 34 Rein KS, Gawley RE. J. Org. Chem. 1991; 56: 1564
- 35 Gawley RE, Zhang PS. J. Org. Chem. 1996; 61: 8103
- 36 Gawley RE, Smith GA. ARKIVOC 2011; 167
- 37 Lohmann J.-J, Seebach D, Syfrig MA, Yoshifuji M. Angew. Chem., Int. Ed. Engl. 1981; 20: 128 ; Angew. Chem. 1981, 93, 125
- 38 Seebach D, Lohmann J.-J, Syfrig MA, Yoshifuji M. Tetrahedron 1983; 39: 1963
- 39 Seebach D, Syfrig MA. Angew. Chem., Int. Ed. Engl. 1984; 23: 248 ; Angew. Chem. 1984, 96, 235
- 40 Seebach D, Huber IM. P, Syfrig MA. Helv. Chim. Acta 1987; 70: 1357
- 41 Burton AJ, Graham JP, Simpkins JP. Synlett 2000; 1640
- 42 Meyers AI, Fuentes LM, Kubota Y. Tetrahedron 1984; 40: 1361
- 43 Meyers AI, Dickman DA, Boes M. Tetrahedron 1987; 43: 5095
- 44 Meyers AI, Warmus JS, Gonzalez MA, Guiles J, Akahane A. Tetrahedron Lett. 1991; 32: 5509
- 45 Beak P, Zajdel WJ. Chem. Rev. 1904; 84: 471
- 46 Bräse S, Enders D, Köbberling J, Avemaria F. Angew. Chem. Int. Ed. 1998; 110: 3614
- 47 Nicolaou KC, Takayanagi M, Jain NF, Natarajan S, Koumbis AE, Bando T, Ramanjulu JM. Angew. Chem. Int. Ed. 1998; 110: 2881
- 48 Hooper DL, Pottier IR, Vacheresse M, Vaughan K. Can. J. Chem. 1998; 76: 125
- 49 Nicolaou KC, Boddy CN. C, Natarajan S, Yue TY, Li H, Bräse S, Ramanjulu JM. J. Am. Chem. Soc. 1997; 119: 3421
- 50 Stevens MF. G, Philipp KS, Rathbone DL, O’Shea DM, Queener SF. J. Med. Chem. 1997; 40: 1886
- 51 Gross ML, Blank DH, Welch WM. J. Org. Chem. 1993; 58: 2104
- 52 Lazny R, Sienkiewiez M, Bräse S. Tetrahedron 2001; 57: 5825
- 53 Wanner MJ, Koch M, Koomen GJ. J. Med. Chem. 2004; 47: 6875
- 54 Enders D, Rijksen C, Bremus-Kobberling E, Gillner A, Kobberling J. Tetrahedron Lett. 2004; 45: 2839
- 55 Lazny R, Nodzewska A, Klosowski P. Tetrahedron 2004; 60: 121
- 56 Bräse S. Acc. Chem. Res. 2004; 37: 805
- 57 Bräse S, Dahmen S, Pfefferkorn M. J. Comb. Chem. 2000; 2: 710
- 58 Bräse S, Kobberling J, Enders D, Lazny R, Wang M, Brandtner S. Tetrahedron Lett. 1999; 40: 2105
- 59 Newlands ES, Stevens MF. G, Wedge SR, Wheelhouse RT, Brock C. Cancer Treat Rev. 1997; 23: 35
- 60 Biscussi B, Sequeira MA, Richmond V, Mañez PA, Murray AP. J. Photochem. Photobiol., A 2021; 418: 113375
- 61 Giampietro L, Gallorini M, Gambacorta N, Ammazzalorso A, Filippies BD, Valle AD, Fantacuzzi M, Maccallini C, Mollica A, Cataldi A, Nicolotti O, Amoroso R. Eur. J. Med. Chem. 2021; 224: 113737
- 62 Kasare MS, Dhavan PP, Shaikh AH. I, Jadhav BL, Pawar SD. J. Mol. Struct. 2022; 35: 2976
- 63 Hall MB, Sadu SS, Kinni M. World J. Pharm. Pharm. Sci. 2015; 4: 1516
- 64 Halli MB, Mallikarjun K, Sadu SS. J. Chem. Pharm. Res. 2015; 7: 1797
- 65 Petrović M, Scarpi D, Nieger M, Jung N, Occhiatob EG, Brӓse S. RSC Adv. 2017; 7: 9461
- 66 Zhang T, Wang Y, Wang B, Jin W, Xia Y, Liu C. Adv. Synth. Catal. 2022; 364: 1962
- 67 Singh KN, Singh P, Kaur M, Sharma E. ChemistrySelect 2017; 2: 2213
- 68 Singh KN, Singh P, Kaur A. Synth. Commun. 2006; 36: 3339
- 69 Preparation of 3,4-Dihydro-(1H-isoquinolin-2-yl)-phenyldiazene (3a) The reaction of phenyldiazonium tetrafluoroborate salt (2a, 10 g, 52 mmol) with 1,2,3,4-tetrahydroisoquinoline (1a, 6.9 g, 52 mmol) in pyridine (9.4 mL) according to the general procedure52 and subsequent purification gave 3a (7.3 g, 60%) as orange solid; mp 58–60 °C. IR (neat): 3023, 2954, 1667, 1584 (N=N stretching), 1452, 1410, 1297, 1153, 1069, 940, 894, 737, 686 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.51–7.44 (m, 2 H), 7.40–7.31 (m, 2 H), 7.27–7.13 (m, 5 H), 4.95 (s, 2 H), 4.10 (t, J = 6.0 Hz, 2 H), 3.06 (t, J = 6.0 Hz, 2 H). 13C NMR (MHz, CDCl3): δ = 150.88, 134.82, 132.56, 128.80, 128.49,127.21, 126.84, 126.57, 125.79, 120.42, 48.27, 29.59. HRMS (ESI): m/z [M + H]+ calcd for C15H15N3: 238.1338; found: 238.1333.
- 70 Zarei A, Khazdooz L, Aghaei H, Azizi G, Chermahini AN, Hajipour AR. Dyes Pigm. 2014; 101: 295
- 71 Typical Procedure B for α-Lithiation and Substitution of 3 Into a flame-dried two-necked round-bottomed flask, equipped with a magnetic stirrer bar, septum cap, and a bubbler, was taken a solution of (3,4-dihydro-1H-isoquinolin-2-yl)-phenyldiazene (0.5 g) in dry THF (3 mL/mmol) under an inert nitrogen atmosphere. It was cooled to –78 °C and s-BuLi (1.2 equiv) was added dropwise. The deep red color (indicative of benzylic carbanion formation) appeared immediately. The solution was stirred at –78 °C for 30 min, and the electrophile (1.2 equiv) was added slowly at the same temperature. The reaction mixture was allowed to warm gradually up to –40 °C. The reaction was quenched with saturated NH4Cl solution, and the contents were poured into Et2O (20 mL). The organic layer was separated, and the aqueous layer was further extracted with Et2O (2 × 10 mL). The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain the crude product. Further purification by column chromatography using silica gel over hexane/ethyl acetate (9:1) afforded the desired C-1-substituted product 4.
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72
Preparation of Diphenyl-(2-phenyldiazenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-methanol (4a)
Reaction of amine 3a (0.5 g, 2.1 mmol) with benzophenone (0.45 g, 2.5 mmol) according to the general procedure71 and subsequent purification with flash chromatography using hexane/ethyl acetate (95:5) gave 4a (0.72 g, 82%) as a white solid; mp 140–142 °C. IR (neat): 3394 (O–H stretching), 3054, 3024, 2937, 1595 (N=N stretching), 1485, 1452, 1423, 1351, 1262, 1220, 1187, 1146, 1107, 1055, 1028, 979, 941, 892, 850, 818, 758, 737, 691, 659, 643 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.69–7.65 (m, 2 H), 7.57 (d, J = 7.7 Hz, 2 H), 7.36–7.25 (m, 10 H), 7.19–7.12 (m, 4 H), 6.92–6.85 (m, 1 H), 6.52 (s, 1 H), 4.03 (q, J = 6.6 Hz, 2 H), 2.91 (d, J = 6.7 Hz, 2 H). 13C NMR (126 MHz, CDCl3): δ = 150.50, 143.73, 136.84, 132.27, 128.78, 128.54, 128.20, 127.35, 126.88, 125.81, 120.85, 82.72, 60.46, 27.72. HRMS (ESI): m/z [M + H]+ calcd for C28H25N3O: 420.2069; found: 420.2071. - 73 Preparation of 1-Benzoyl-2-phenyldiazenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-phenylmethanone (4g) Reaction of amine 3a (0.5 g, 2.1 mmol) with ethyl benzoate (0.61 mL, 4.2 mmol) according to the general procedure71 and subsequent purification with flash chromatography using hexane/ethyl acetate (95:5) gave 4g (0.68 g, 72%) as a yellow oil. IR (neat): 3059, 2926, 1715 (C=O stretching), 1668 (C=O stretching), 1596 (N=N), 1494, 1448, 1427, 1372, 1245, 1229, 1157, 1123, 1026, 1000, 922, 828, 744, 718, 692, 636 cm–1. 1H NMR (500 MHz, DMSO): δ = 7.74–7.69 (m, 2 H), 7.51–7.49 (m, 3 H), 7.46–7.38 (m, 4 H), 7.38–7.22 (m, 8 H), 7.11–7.06 (m, 2 H), 6.74 (dd, J = 17.5, 11.0 Hz, 1 H), 5.70 (dd, J = 17.5, 1.3 Hz, 1 H), 5.12 (dd, J = 11.0, 1.2 Hz, 1 H), 4.03 (m, J = 7.1 Hz, 1 H). 13C NMR (126 MHz, DMSO): δ = 170.16, 143.71, 136.40, 136.11, 135.27, 134.23, 131.66, 130.95, 129.54, 129.27, 128.93, 128.69, 128.29, 127.49, 126.47, 125.43, 125.02, 121.87, 115.23, 113.62, 59.58, 42.42, 27.56.
- 74 General Procedure C for the Deprotection of 4/7 Using Trifluoroacetic Acid (TFA)52 Into a 50 mL round-bottom flask equipped with magnetic bar and guard tube was taken a solution of 4/7 (100 mg, 1 equiv) in dry ethanol (2 mL/mmol). The solution was cooled to 0 °C, and trifluoroacetic acid (TFA, 20 equiv) was added slowly to the solution. The reaction mixture was allowed to warm to room temperature and further stirred overnight. Solvent was evaporated under reduced pressure. The residue, so obtained, was basified with 20% potassium hydroxide solution and extracted with chloroform (4 × 10 mL). The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo to afford the crude deprotected product. Purification by flash chromatography using 230–400 silica gel using chloroform/methanol (9:1) to afford α-substituted product 5 and 8.
- 75 Preparation of Phenyl-(1-phenyl-3,4-dihydro-1H-isoquinolin-2-yl)-diazene (7a) Reaction of amine 3a (0.5 g, 2.1 mmol) with chlorobenzene (6a, 0.64 mL, 6.3 mmol) according to the general procedure76 and subsequent purification with flash chromatography using hexane/ethyl acetate (95:5) gave 7a as a yellow oil (0.42 g, 65%). IR (neat): 3026, 2874, 1590 (N=N), 1484, 1412, 1350, 1167, 1103, 1069, 1024, 911, 865, 757, 731, 713, 689 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.40 (d, J = 8.0 Hz, 2 H), 7.27 (t, J = 7.7 Hz, 2 H), 7.18 (q, J = 8.9 Hz, 9 H), 7.08 (t, J = 7.3 Hz, 1 H), 6.58 (s, 1 H), 4.13 (dt, J = 13.7, 6.8 Hz, 1 H), 3.93–3.86 (m, 1 H), 2.99 (dt, J = 13.5, 6.2 Hz, 1 H), 2.84 (dt, J = 15.3, 6.3 Hz, 1 H). 13C NMR (126 MHz, CDCl3): δ = 141.57, 135.27, 128.95, 128.85, 128.47, 128.15, 127.79, 127.54, 127.37, 126.57, 125.68, 120.72, 53.43, 43.27, 27.88. HRMS (ESI): m/z [M + H]+: C21H19N3 calcd for 314.1651; found: 314.1653.
- 76 General Procedure for Arylation of 3 Into a flame-dried two-necked round-bottomed flask (50 mL), equipped with a magnetic stirrer bar, septum cap, and a bubbler, was taken a solution of (3,4-dihydro-1H-isoquinolin-2-yl)-phenyldiazene (3, 0.5 g) in dry THF (3 mL/mmol) under an inert nitrogen atmosphere. It was cooled to –78 °C, and s-BuLi (1.2 equiv) was added. A deep red color, which is indicative of benzylic carbanion formation, appeared immediately. The solution was stirred at the same temperature for 30 min. The second installment of s-BuLi (3 equiv) was added, followed by addition of a solution of arylhalide 6 (3 equiv) in THF (1 mL). The reaction mixture was stirred at –78 °C for 30 min and was allowed to warm to 0 °C slowly over a period of 4–5 h. The reaction was quenched with saturated NH4Cl solution, and the contents were poured into Et2O (20 mL). The organic layer was separated, and the aqueous layer was further extracted with Et2O (2 × 10 mL). The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to afford the crude product which was purified by flash chromatography using 230–400 mesh silica gel. Elution with ethyl acetate/hexane (1:9) afforded the product 7.
For a review on functionalization of piperidines, see: