Organocatalytic Friedel–Crafts Benzylation of Heteroaromatic and Aromatic Compounds via an S_N1 Pathway

Abstract

The Friedel–Crafts-type benzylation of various π-excessive heteroaromatic and aromatic compounds with trityl or benzhydryl halides was efficiently promoted by a thiourea catalyst. This is a novel example of thiourea catalysis of aromatic alkylation by way of an S_N1 pathway.

Key words

benzylation - catalysis - heterocycles - arenes

• References and Notes

• 1a Friedel–Crafts and Related Reactions: General Aspects . Vol. II, Part I. Olah GA. Wiley-Interscience; New York: 1964
• 1b Roberts RM, Khalaf AA. Friedel–Crafts Alkylation Chemistry: A Century of Discovery . Marcel Dekker; New York: 1984
• 1c Olah GA. A Life of Magic Chemistry: Autobiographical Reflections of a Nobel Prize Winner. Wiley-Interscience; New York: 2001
• 2 Smith MB. March’s Advanced Organic Chemistry . John Wiley; Hoboken: 2013. 7th ed., 609-615

For reviews, see:
• 3a Bandini M, Melloni A, Tommasi S, Umani-Ronchi A. Synlett 2005; 1199
• 3b Almasi D, Alonso DA, Nájera C. Tetrahedron: Asymmetry 2007; 18: 299
• 3c Vicario JL, Badía D, Carrillo L. Synthesis 2007; 2065
• 3d You S.-L, Cai Q, Zeng M. Chem. Soc. Rev. 2009; 38: 2190
• 3e Terrasson V, Marcia de Figueiredo R, Campagne JM. Eur. J. Org. Chem. 2010; 2635
• 3f Lu H.-H, Tan F, Xiao W.-J. Curr. Org. Chem. 2011; 15: 4022
• 3g Lu L.-Q, Chen J.-R, Xiao W.-J. Acc. Chem. Res. 2012; 45: 1278

For monographs, see:
• 4a Berkessel A, Gröger H. Asymmetric Organocatalysis: From Biomimetic Concepts to Applications in Asymmetric Synthesis. Wiley-VCH; Weinheim: 2005
• 4b Enantioselective Organocatalysis: Reactions and Experimental Procedures. Dalko PI. Wiley-VCH; Weinheim: 2007
• 4c Science of Synthesis: Asymmetric Organocatalysis: Workbench Edition. Vol. 1. List B. Thieme; Stuttgart: 2012
• 4d Science of Synthesis: Asymmetric Organocatalysis: Workbench Edition. Vol. 2. Maruoka K. Thieme; Stuttgart: 2012
• 4e Comprehensive Enantioselective Organocatalysis. Dalko PI. Wiley-VCH; Weinheim: 2013
• 5a McCubbin JA, Hosseini H, Krokhin OV. J. Org. Chem. 2010; 75: 959
• 5b McCubbin JA, Krokhin OV. Tetrahedron Lett. 2010; 51: 2447
• 5c McCubbin JA, Nassar C, Krokhin OV. Synthesis 2011; 3152

See also:
• 5d Zheng H, Ghanbari S, Nakamura S, Hall DG. Angew. Chem. Int. Ed. 2012; 51: 6187
• 6a Westmark PR, Gardiner SJ, Smith BD. J. Am. Chem. Soc. 1996; 118: 11093
• 6b Kheirjou S, Abedin A, Fattahi A. Comput. Theor. Chem. 2012; 1000: 1

For a review, see:
• 7a Zhang Z, Schreiner PR. Chem. Soc. Rev. 2009; 38: 1187

For some recent examples on halide anion capture in thiourea catalysis, see:
• 7b Raheem IT, Thiara PS, Peterson EA, Jacobsen EN. J. Am. Chem. Soc. 2007; 129: 13404
• 7c Reisman SE, Doyle AG, Jacobsen EN. J. Am. Chem. Soc. 2008; 130: 7198
• 7d De CK, Klauber EG, Seidel D. J. Am. Chem. Soc. 2009; 131: 17060
• 7e Knowles RR, Lin S, Jacobsen EN. J. Am. Chem. Soc. 2010; 132: 5030
• 7f Brown AR, Kuo W.-H, Jacobsen EN. J. Am. Chem. Soc. 2010; 132: 9286
• 7g Birrell JA, Desrosiers J.-N, Jacobsen EN. J. Am. Chem. Soc. 2011; 133: 13872
• 7h Min C, Mittal N, De CK, Seidel D. Chem. Commun. 2012; 48: 10853

For our previous works on thiourea-based organocatalysis, see:
• 8a Mori K, Maddaluno J, Nakano K, Ichikawa Y, Kotsuki H. Synlett 2009; 2346
• 8b Mori K, Maddaluno J, Nakano K, Ichikawa Y, Kotsuki H. Synlett 2011; 2080
• 8c Sasakura N, Nakano K, Ichikawa Y, Kotsuki H. RSC Adv. 2012; 2: 6135
• 8d Moritaka M, Miyamae N, Nakano K, Ichikawa Y, Kotsuki H. Synlett 2012; 23: 2554
• 9 Jakab G, Tancon C, Zhang Z, Lippert KM, Schreiner PR. Org. Lett. 2012; 14: 1724
• 10 As expected, the use of TrOH in place of TrCl was ineffective in this transformation.
• 11 2-Tritylfuran (6) and 2,5-Ditritylfuran (7); Typical Procedure (Table 1, Entry 4) Catalyst 1 (50.0 mg) and powdered activated 3 Ǻ MS (10 mg) were added to a colorless solution of Ph₃CCl (5, 279 mg, 1.0 mmol) and freshly distilled furan (340 mg, 5.0 mmol) in dry CH₂Cl₂ (2.0 mL), and the mixture was stirred for 4 h at r.t. At the end of the reaction, the solution became reddish purple. The mixture was concentrated and the residue was purified by column chromatography [silica gel, hexane–Et₂O (50:1 to 10:1)] to give 6 and 7. 2-Tritylfuran (6) Colorless needles; yield: 186 mg, (60%); mp 201–202 °C (hexane–Et₂O); R_f = 0.24 (hexane). FTIR (KBr): 1595, 1490, 1442 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 6.04 (dd, J = 2.0, 1.0 Hz, 1 H), 6.32 (dd, J = 2.0, 1.5 Hz, 1 H), 7.06–7.11 (m, 6 H), 7.22–7.28 (m, 9 H), 7.45 (br s, 1 H). ¹³C NMR (125.8 MHz, CDCl₃): δ = 60.84, 109.78, 111.31, 126.58 (×3), 127.60 (×6), 130.20 (×6), 142.25, 145.14 (×3), 159.28. Anal. Calcd for C₂₃H₁₈O: C, 89.00; H, 5.85. Found: C, 89.15; H, 5.47. 2,5-Ditritylfuran (7) Colorless needles; yield: 108 mg (39%); mp >280 °C (sublimed, CHCl₃); R_f = 0.15 (hexane). FTIR (KBr): 1594, 1492, 1444 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 5.96 (s, 2 H), 6.98–7.05 (m, 12 H), 7.15–7.25 (m, 18 H). ¹³C NMR (125.8 MHz, CDCl₃): δ = 60.92 (×2), 110.92 (×2), 126.35 (×6), 127.52 (×12), 130.27 (×12), 144.85 (×6), 159.51 (×2). Anal. Calcd for C₄₂H₃₂O·H₂O: C, 88.39; H, 6.00. Found: C, 88.58; H, 5.75.
• 12a The use of molecular sieves as acid scavengers is well established; see: Encyclopedia of Reagents for Organic Synthesis . Vol. 9. Paquette LA, Crich D, Fuchs PL, Molander GA. Wiley; Chichester: 2009. 2nd ed., 7162–7165
• 12b Unfortunately, the same reaction in the presence of a tertiary amine base such as Et₃N as an acid scavenger gave a rather complex mixture of products, and the yields were not determined.
• 13 When the same reaction was conducted by adding 10 mol% of TBACl, the reaction was completely suppressed, indicating the important contribution of the common-ion effect.
• 14 Judging from this result, there is some possibility that 3 Ǻ MS not only acted as an acid scavenger, but also an accelerator.
• 15 Judging from the result shown in entry 9 of Table 1, we were obliged to conclude that diphenylthiourea 3 acted as a catalyst poison in this system.
• 16 We did not check the recyclability of catalyst 1. However, after the reaction was complete, in most cases 1 could be clearly detected by TLC and should be recoverable.
• 17 In a control experiment (Table 2, entry 1), only a trace amount of products was formed in the absence of catalyst 1 (36 h in refluxing DCE).
• 18 Unfortunately, the product distribution did not change when the reaction was performed in the presence of a radical inhibitor such as hydroquinone (6 h in refluxing DCE): 14 (44%), 15 (17%), and Ph₃CH (20%). This product distribution is similar to that obtained the presence of a radical initiator such as AIBN: 14 (45%), 15 (8%), and Ph₃CH(26%). Importantly, the formation of furanylmethyl radicals has only been noted under conditions of photo-irradiation. See, for example: Cantrell TS, Allen AC, Ziffer H. J. Org. Chem. 1989; 54: 140
• 19 All attempts to perform the tritylation of 1,4-dimethoxy-benzene in the presence of catalyst 1 failed for reasons that are not yet clear.
• 20 For example, see: Zhang J, Bellomo A, Creamer AD, Dreher SD, Walsh PJ. J. Am. Chem. Soc. 2012; 134: 13765
• 21 In a control experiment (Table 3, entry 2), the reaction was significantly retarded in the absence of catalyst 1 (6 h in refluxing DCE), and gave 25% of 27 along with 7% of 28.
• 22 We cannot exclude the possibility that an S_N2-type mechanism might also operate in reactions with 8 as the electrophile. At present, we have no clear idea of the halophilic strength (Br versus Cl) of catalyst 1.