Dual Electrophilic Trapping-Negishi Coupling with Dilithiothiophenes in a Three-Component, One-Pot Process

Abstract

Based upon a twofold bromine-lithium exchange with 2,5-dibromo thiophene and sequential trapping of the dilithio intermediate, organo zinc halides were generated in situ and subsequently transformed by Negishi cross-coupling to unsymmetrically substituted thiophenes in a one-pot fashion. Application of this novel sequence to diiodo(hetero)arenes quickly furnishes highly interesting building blocks for materials science applications.

arenes - C-C coupling - heterocycles - lithiation - multicomponent reactions

References and Notes

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<A NAME="RG39809ST-4A">4a</A> Knochel P. Calaza MI. Hupe E. Negishi E.-I. Liu F. In Metal-Catalyzed Cross-Coupling Reactions   de Meijere A. Diederich F. Wiley-VCH; Weinheim: 2004.  p.619-670  

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<A NAME="RG39809ST-6">6</A>

Representive Procedure: Synthesis of 3b (Table 1, Entry 2) In a flame-dried Schlenk flask under argon atmosphere n-BuLi (1.6 M in n-hexane, 2.5 mL, 4.0 mmol) and TMEDA (0.6 mL, 4.0 mmol) were dissolved in anhyd THF (80 mL) at -78 ˚C. 2,5-Dibromothiophene (1, 484 mg, 2.0 mmol) was added slowly to the solution, and the mixture was stirred for 30 min. Then, TMSCl (217 mg, 2.0 mmol) in anhyd THF (20 mL) was added dropwise to the stirred solution over a period of 3 h. The reaction mixture was stirred for another 30 min, and ZnBr₂ (496 mg, 2.2 mmol) in anhyd THF (10 mL) was added. After stirring for 15 min the reaction mixture was allowed to warm to r.t. and stirred for another 20 min. 1-Iodo-3,5-dimethylbenzene (510 mg, 2.2 mmol) in anhyd THF (5 mL) and Pd(PPh₃)₄ (5 mol%) were added. The solution was stirred at r.t. for 16 h. The solvent was removed under reduced pressure and the residue purified by flash chromatography on silica gel (n-hexane) yielding 280 mg (54%) of 3b as a colorless oil. ^¹H NMR (500 MHz, CDCl₃): δ = 0.32 (s, 9 H), 2.33 (s, 6 H), 6.90 (s, 1 H), 7.18 (d, ^³ J = 3.3 Hz, 1 H), 7.23 (s, 2 H), 7.31 (d, ^³ J = 3.3 Hz, 1 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 0.1 (CH₃), 21.5 (CH₃), 124.2 (CH), 129.4 (CH), 134.5 (C_q), 135.1 (C_q), 138.5 (CH), 139.8 (C_q), 150.2 (C_q). MS (EI, 70 eV): m/z (%) = 260 (44) [M]⁺, 245 (100) [C₁₄H₁₇SSi]⁺, 215 (5) [C₁₂H₁₁SSi]⁺, 123 (9), 115 (43). IR (KBr): ν = 544 (w), 561 (w), 608 (w), 623 (w), 652 (w), 692 (m), 756 (m), 802 (s), 842 (s), 947 (w), 990 (s), 1055 (m), 1182 (w), 1212 (m), 1250 (s), 1323 (w), 1377 (w), 1438 (m), 1526 (w), 1601 (m), 1760 (w), 2858 (m), 2925 (m), 2956 (m) cm^-¹. UV/Vis (CH₂Cl₂): λ_max (ε) = 294 (12700), 314 (21800) nm. Anal. Calcd for C₁₅H₂₀SSi (260.5): C, 69.17; H, 7.74. Found: C, 69.34; H, 7.60.

<A NAME="RG39809ST-7">7</A>

Representive Procedure: Synthesis of Terthiophene 4a In a flame-dried Schlenk flask under argon atmosphere n-BuLi (1.6 M in n-hexane, 2.5 mL, 4.0 mmol) and TMEDA (0.6 mL, 4.0 mmol) were dissolved in anhyd THF (80 mL) at -78 ˚C. 2,5-Dibromothiophene (1, 484 mg, 2.0 mmol) was added slowly to the solution, and the mixture was stirred for 30 min. Then, TMSCl (217 mg, 2.0 mmol) in anhyd THF (20 mL) was added dropwise to the stirred solution over a period of 3 h. The reaction mixture was stirred for another 30 min, and ZnBr₂ (496 mg, 2.2 mmol) in anhyd THF (10 mL) was added. After stirring for 15 min the reaction mixture was allowed to warm to r.t. and stirred for another 20 min. Finally, 2,5-diiodothiophene (269 mg, 0.8 mmol) and Pd(PPh₃)₄ (5 mol%) were added. The solution was stirred at r.t. for 16 h and afterwards the solvent removed under reduced pressure and the residue purified by flash chromatography on silica gel (n-hexane) yielding 200 mg (67%) of 3a as a light yellow solid. ^¹H NMR (500 MHz, CDCl₃): δ = 0.32 (s, 18 H), 7.06 (s, 2 H), 7.12 (d, ^³ J = 3.4 Hz, 2 H), 7.20 (d, ^³ J = 3.4 Hz, 2 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 0.1 (CH₃), 124.6 (CH), 125.1 (CH), 135.0 (CH), 136.5 (C_q), 140.2 (C_q), 142.4 (C_q). MS (EI, 70 eV): m/z (%) = 393 (2.5) [M]⁺, 320 (47), 305 (46), 261 (47), 215 (49), 203 (12), 184 (12), 171 (36), 137 (17), 115 (100), 109 (10).

<A NAME="RG39809ST-8A">8a</A> Handbook of Oligo- and Polythiophenes   Fichou D. Wiley-VCH; Weinheim: 1998. 

<A NAME="RG39809ST-8B">8b</A> Bäuerle P. In Electronic Materials: The Oligomer Approach   Müllen K. Wegner G. Wiley-VCH; Weinheim: 1998.  p.105-197  

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<A NAME="RG39809ST-10A">10a</A> Hou J. Chen H.-Y. Zhang S. Li G. Yang Y. J. Am. Chem. Soc.  2008,  130:  16144 

<A NAME="RG39809ST-10B">10b</A> Li C. Shi J. Xu L. Wang Y. Cheng Y. Wang H. J. Org. Chem.  2009,  74:  408 

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<A NAME="RG39809ST-11A">11a</A> Ebata H. Miyazaki E. Yamamoto T. Takimiya K. Org. Lett.  2007,  9:  4499 

<A NAME="RG39809ST-11B">11b</A> Bossi A. Maiorana S. Graiff C. Tiripicchio A. Licandro E. Eur. J. Org. Chem.  2007,  4499 

<A NAME="RG39809ST-12">12</A>

Synthesis of 3b Starting from Thiophene In a flame-dried, three-neck flask under argon atmosphere n-BuLi (1.6 M in n-hexane, 6 mL, 8.8 mmol), TMEDA (1.2 mL, 8.0 mmol), and thiophene (340 mg, 4.0 mmol) were dissolved in n-hexane (20 mL). The reaction mixture was heated to reflux for 1.5 h. After complete deprotonation, the mixture was allowed to cool to r.t. and was then cooled to
-78 ˚C. THF (130 mL) was given to the content of the flask. Then TMSCl (430 mg, 4.0 mmol) in anhyd THF (20 mL) was added dropwise to the stirred solution over a period of 3 h. The reaction mixture was stirred for another 30 min, and ZnBr₂ (496 mg, 2.2 mmol) in anhyd THF (10 mL) was added. After stirring for 15 min the reaction mixture was allowed to warm to r.t. and stirred for another 20 min. Finally, 1-iodo-3,5-dimethylbenzene (1029 mg, 4.4 mmol) in anhyd THF (10 mL) and Pd(PPh₃)₄ (5 mol%) were added. The solution was stirred at r.t. for 16 h and afterwards the solvent removed under reduced pressure and the residue purified by flash chromatography on silica gel (n-hexane) yielding 406 mg (39%) of 3b as a colorless oil.

<A NAME="RG39809ST-13">13</A> Franz AW. Müller TJJ. Synthesis  2008,  1121