A 1,3‐Lithium Shift of Propargylic/Allenylic Lithium and the Subsequent Transmetalation Coupling Reaction with Aryl Halides

Abstract

The lithiation reagent and temperature may be the key factors controlling the 1,3-lithium shift of propargylic/allenylic lithium (see scheme). Under the right conditions, 1,1-diarylallenes and 1,3-diarylallenes can be easily and highly selectively synthesized by the lithiation of 1-aryl-1-alkynes and the subsequent transmetalation (1), and Pd-catalyzed coupling with aryl halides (2). Selective synthesis has been a formidable challenge in organic synthesis, especially controlled highly selective synthesis beginning from the same starting materials.1 Herein, we report a novel clean 1,3-lithium shift reaction of propargylic/allenylic lithium (Scheme 1). Based on this observation, the corresponding sequential transmetalation and Pd-catalyzed coupling with aryl halides leading to 1,1-diarylallenes (1) or 1,3-diarylallenes (2) highly selectively from the same 1-aryl-1-alkynes has been developed (Scheme 1). Protocol for the selective synthesis of 1,1-diarylallenes or 1,3-diarylallenes by monolithiation of 1-aryl-1-alkynes, transmetalation, and Pd-catalyzed coupling with aryl halides. Recently, we developed a monolithiation reaction of 1-aryl-1-alkynes with or without the mediation of HgCl2.2, 3 The propargylic/allenylic lithium formed in this reaction undergoes sequential transmetalation and Pd-catalyzed coupling with organic halides leading to alkynes or allenes depending on the structures of the starting materials.4 Quite recently, however, we observed that the sequential monolithiation of 1-aryl-1-alkynes beyond 1-aryl-1-propyne, (1-phenyl-1-butyne), the transmetalation, Pd-catalyzed coupling reaction with aryl halides when conducted by different chemists, or even the same chemist at different times, surprisingly gave two products. These products were identified as allenes 1 a and 2 a and formed in very different ratios ranging from 0:100 to 100:0; in other words, in terms of the ratio of 1 a to 2 a, the results were difficult to reproduce (entries 1 and 2, Table 1). Entry T[a] Yield[b] (1 a/2 a) nBuLi tBuLi LDA 1 8 °C 100:0–0:100 100:0–0:100 84 %[c] (0:100) 2 −10 °C 100:0–0:100 54 % (89:11) – 3 −20 °C 70 % (100:0) 28 % (93:7) 98 % (0:100) 4 −40 °C 54 % (100:0) 54 % (100:0) 96 % (19:81) 5 −55 °C – – 94 % (45:55) 6 −65 °C – – 88 % (77:23) 7 −78 °C no lithiation no lithiation 50 % (91:9) Further investigations showed that with different lithiation reagents, the ratios of 1 a and 2 a are also different, some of the representative results are summarized in Table 1 with the following noteworthy points: (1) No lithiation was observed with nBuLi or tBuLi at −78 °C (entry 7, Table 1); (2) Lithiation with LDA at −78 °C followed by transmetalation and coupling afforded 1 a and 2 a in 50 % yield with a ratio of 91:9 (entry 7, Table 1). Lithiation with LDA at a higher temperature favors the formation of 2 a; (3) lithiation with nBuLi or tBuLi at −20 °C or −40 °C led to the highly selective or exclusive formation of the nonisomerized product 1 a (entries 3 and 4, Table 1). These facts indicate that the temperature and amine may be the factors that control the isomerization of 1-aryl-1-alkyn-3-yl or 1-aryl-1,2-alkadien-1-yl lithium to 1-aryl-2-alkyn-1-yl or 1-aryl-1,2-alkadien-3-yl lithium, respectively (Scheme 1). In fact, it was observed that when the lithiation of 1-phenyl-1-butyne was conducted at −20 °C for 1 h then at room temperature for 2 h, instead of 1,1-diphenyl-1,2-butadiene (1 a), the sequential reaction afforded 1,3-diphenyl-1,2-butadiene (2 a) in 74 % yield (Scheme 2). With a longer reaction time for the lithiation at room temperature, the yields of 1 a and 2 a decreased dramatically. When the lithiation was performed at −20 °C for 1 h followed by the addition of N,N,N′,N′-tetramethyl ethylene diamine (TMEDA) at −20 °C, the same sequential reaction also afforded the isomerized product 1,3-diphenyl-1,2-butadiene (2 a) in 94 % yield, thus indicating an interesting effect of amine on the 1,3-lithium shift (Scheme 3). Different lithiation conditions gave different ratios of 1 a/2 a. The effect of TMEDA on the 1,3-lithium shift. Through trial and error, we were happy to identify two suitable sets of reaction conditions: A) lithiation at −20 °C with nBuLi for 1 h followed by transmetalation (ZnBr2 was added at −20 °C followed by stirring at room temperature) and coupling at room temperature for the selective formation of 1,1-diarylallenes; B) lithiation at room temperature with LDA for 1 h followed by transmetalation and coupling at room temperature for the selective formation of 1,3-diarylallenes. Under conditions A and B, the results can be easily reproduced. Some typical results are presented in Table 2, which indicates that: 1) the reaction is general for differently substituted 1-aryl-1-alkynes/aryl halides; 2) the regioselectivity for the formation of 1,1-diarylallenes and 1,3-diarylallenes is excellent. Entry Ar1 CH2R Ar2I Base T [°C] Yield [%][a] (1/2) 1 Ph C2H5 C6H5I nBuLi −20 55 (1 a:2 a=100:0) 2 Ph C2H5 C6H5I LDA 8 84 (1 a:2 a=0:100) 3 Ph C4H9 C6H5I nBuLi −20 71 (1 b:2 b=99:1) 4 Ph C4H9 C6H5I LDA 10 89 (1 b:2 b=0:100) 5 Ph C4H9 p-MeC6H4I nBuLi −20 79 (1 c:2 c=99:1) 6 Ph C4H9 p-MeC6H4I LDA 20 99 (1 c:2 c=0:100) 7 Ph C4H9 α-C10H8I nBuLi −20 63 (1 d:2 d=100:0) 8 Ph C4H9 α-C10H8I LDA 20 56 (1 d:2 d=0:100) 9 Ph C4H9 p-MeOC6H4I nBuLi −20 74 (1 e:2 e=98:2) 10 Ph C4H9 p-MeOC6H4I LDA 30 83 (1 e:2 e=0:100) 11 Ph C4H9 p-MeO2CC6H4I nBuLi −20 93 (1 f:2 f=100:0) 12 Ph C4H9 p-MeO2CC6H4I LDA 19 71 (1 f:2 f=0:100) 13 Ph C3H7 C6H5I nBuLi −20 76 (1 g:2 g=100:0) 14 Ph C3H7 C6H5I LDA 11 96[b] (1 g:2 g=0:100) 15 p-PhC6H4 C3H7 C6H5I nBuLi −20 77 (1 h:2 h=100:0) 16 p-PhC6H4 C3H7 C6H5I LDA 18 72 (1 h:2 h=0:100) In conclusion, we have observed a clean and complete 1,3-lithium shift reaction of 1-aryl-1-alkyn-3-yl or 1-aryl-1,2-alkadien-1-yl lithium leading to 1-aryl-1,2-alkadien-3-yl or 1-aryl-2-alkyn-1-yl lithium, respectively. Although this kind of 1,3-metal shift has been observed,5–7 the present protocol provides a clear-cut control of the lithiation as well as the isomerization. Under conditions A and B, 1,1-diarylallenes and 1,3-diarylallenes, respectively, can be prepared starting from the same alkynes. Although the mechanism of 1,3-lithium shift is not clear, this work may open up a new area for the study and control of 1,3-metal shifts in propargyl/allenylic species. Further investigations in this area are continuing in our laboratory. Typical procedure (conditions A): nBuLi (0.45 mL, 1.6 M in hexanes, 0.72 mmol) was added to a solution of 1-phenyl-1-butyne (78 mg, 0.6 mmol) in THF (3 mL) in a dry Schlenk tube at −20 °C under N2. The reaction mixture was stirred at −20 °C for 1 h, then a solution of dry ZnBr2 (275 mg, 1.2 mmol) in THF (4 mL) was added. After a further 10 min at this temperature the reaction mixture was warmed up to room temperature and kept there for 20 min. [Pd(PPh3)4] (35 mg, 5 mol %) and iodobenzene (83 μL, 0.72 mmol) were subsequently added, and the resulting mixture was stirred at room temperature. After the reaction was complete, as monitored by TLC (eluent: petroleum ether, 60–90 °C), it was quenched with saturated NH4Cl and extracted with ether. The product solution was dried over MgSO4, the solvent was removed by rotary evaporation, and the crude product was purified by flash chromatography on silica gel (petroleum ether) to afford 1 a8 (68 mg, 55 %) as a liquid. 1H NMR (CDCl3, 300 MHz): δ=7.43–7.25 (m, 10 H), 5.72 (q, J=7.1 Hz, 1 H), 1.89 ppm (d, J=7.1 Hz, 3 H); 13C NMR (CDCl3, 75.4 MHz): δ=206.32, 137.24, 128.42, 128.28, 126.98, 109.18, 88.85, 14.33 ppm; MS (70 eV): m/z (%): 206 (84.30) [M+], 191 (100) [M+−CH3]; IR (neat): =1943 cm−1; HRMS calcd for C16H14 [M+]: 206.10955, found: 206.10914. Typical procedure (conditions B): LDA (0.4 mL, 2.0 M in THF/ethylbenzene/pentane, 0.8 mmol) was added to a solution of 1-phenyl-1-butyne (58 mg, 0.45 mmol) in THF (3 mL) in a dry Schlenk tube at room temperature under N2. After the solution had been stirred for 1 h at room temperature, a solution of dry ZnBr2 (499 mg, 2.22 mmol) in THF (4 mL) was added. After a further 25 min at this temperature, [Pd(PPh3)4] (22 mg, 5 mol %) and iodobenzene (42 μL, 0.38 mmol) were added. After the reaction was complete as monitored by TLC (eluent: petroleum ether, 60–90 °C), it was quenched with saturated NH4Cl and extracted with ether. The resulting solution was dried over MgSO4, the solvent was removed by rotary evaporation, and the crude product was purified by flash chromatography on silica gel (petroleum ether) to afford 1 b9 (65 mg, 84 %) as a liquid. 1H NMR (CDCl3, 300 MHz): δ=7.53–7.47 (m, 2 H), 7.40–7.20 (m, 8 H), 6.50 (q, J=2.7 Hz, 1 H), 2.25 ppm (d, J=2.7 Hz, 3 H); 13C NMR (CDCl3, 75.4 MHz): δ=206.77, 136.23, 134.44, 128.67, 128.43, 127.01, 126.99, 126.85, 125.78, 104.48, 96.56, 16.75 ppm; MS (70 eV): m/z (%): 206 (79.98) [M+], 191 (100) [M+−CH3]; IR (neat): =1936 cm−1. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2004/z52924_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.